WO2007052301A2 - Process for the preparation of irbesartan - Google Patents

Process for the preparation of irbesartan Download PDF

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Publication number
WO2007052301A2
WO2007052301A2 PCT/IN2006/000323 IN2006000323W WO2007052301A2 WO 2007052301 A2 WO2007052301 A2 WO 2007052301A2 IN 2006000323 W IN2006000323 W IN 2006000323W WO 2007052301 A2 WO2007052301 A2 WO 2007052301A2
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Prior art keywords
formula
compound
irbesartan
salts
butyl
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PCT/IN2006/000323
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French (fr)
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WO2007052301A3 (en
Inventor
Pandurang Balwant Deshpande
Parvenkumar Luthra
Dhiraj Mohansinh Rathod
Hitesh Kantilal Patel
Pinky Tarak Parikh
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Alembic Limited
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Publication of WO2007052301A3 publication Critical patent/WO2007052301A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present invention relates to a novel synthesis of Irbesartan of formula (I) or its salts.
  • Irbesartan is an angiotensin antagonists and chemically known as 2- «-butyl-4- spirocyclopentane-l-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. It is useful for the treatment of hypertension.
  • the present invention also relates to the process for the preparation of compound of formula (V), which is useful intermediate for the preparation of Irbesartan (I)
  • Angiotensin II is a potent vasopressor and the biologically active product of the rennin- angiotensin system. Renin acts on the angiotensinogen of the plasma to produce angiotensin I, which is converted to angiotensin II by the action of the angiotensin I converting enzyme.
  • Irbesartan is useful as angiotensin antagonists, particularly angiotensin-II antagonists. It inhibits the action of angiotensin II on its receptors and thus prevents the increase in blood pressure produced by the hormone receptor interaction. Thus, Irbesartan is useful for the treatment of hypertension and heart failure.
  • Irbesartan The synthesis of Irbesartan (I) has been described in US Patent no. 5,270,317. Accordingly, the process involves the reaction of 2-n-butyl-4-spirocyclopentane-2- imidazolin-5-one (A) with 4-bromomethyl-2'-cyanobiphenyl (B) in presence of base such as KOH, a metal alcoholate, a metal hydride, calcium carbonate or triethyl amine in inert solvent such as DMF, DMSO or THF to obtain 2-(n-butyl)-3-(2'cyanobiphenyl-4- ylmethyl)-4-oxo-l,3-diazaspiro[4,4]non-l-ene of formula (Va), which is a key intermediate of Irbesartan.
  • base such as KOH, a metal alcoholate, a metal hydride, calcium carbonate or triethyl amine
  • inert solvent such as DMF,
  • compound of formula (Va) is treated with Tributyltinazide in xylene and tritylated to give 2-(n-Butyl)-3-[[2'-(l-trityl-lH-tetrazoyl- 5-yl)biphenyl-4-yl]methyl] ⁇ l,3-diazaspiro[4.4]non-l-en-4-one of formula (Vb), which upon hydrolysis gives Irbesartan as shown in below Scheme (I).
  • US patent no. 6,162,922 disclosed the process for the preparation of Irbesartan involving the reaction of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one (A) with 4- bromomethyl-2'-cyanobiphenyl (B) in presence of a water immiscible solvent, a base and a phase transfer catalyst to give compound of formula (Va), which is subsequently converted to Irbesartan (I).
  • the compound of formula (E) is further treated with 4- aminomethyI-2'-cyanobiphenyl in presence of DCC and N-hydroxysuccinamide to give l-(2'-cyanobiphenyl-4-ylmethylaminocarbonyl)-l-pentanoylaminocycIo ⁇ entane (F), which is cyclized in presence of p-toluenesulfonic acid monohydrate in toluene to give 2- (n-butyl)-3-(2'cyanobiphenyl-4-ylmethyl)-4-oxo-l,3-diazaspiro[4,4]non-l-ene (Va) and finally converted to Irbesartan (I) with the treatment of tributyltin azide.
  • This compound (Vb) is converted to Irbesartan (I) by conventional methods.
  • this approach of the synthesis of Irbesartan (I) is low yielding (about 20%) and requires purification by column chromatography, which is laborious and costlier and not feasible at commercial scale.
  • the object of the present invention is to provide a novel process for the preparation of Irbesartan.
  • the further object of the invention is to provide a novel process for the preparation of compound formula (V), which is an important intermediate for the preparation of Irbesartan (I).
  • Still another object of the invention is to a provide novel compound 1 -[2-( 1 -Trityl- 1 H- tetrazol-5 -yl-4 ' -methylaminocarbonyl-biphenyl] - 1 -pentanoylamino cyclopentane of formula (IVb)
  • the object of the present invention is to provide a novel process for the preparation of Irbesartan and its intermediate, which is simple and easy to handle and cost effective.
  • the present invention provides a novel process for the preparation of Irbesartan of formula (I) or its salts, which comprises
  • the present invention provides a process for the preparation of Irbesartan of formula (I) or its salts comprising the steps of
  • the present invention provides a further process for the preparation of Irbesartan (I) or its salts comprises the steps of
  • the present invention also provides a novel process for the preparation of the compound of formula (V),
  • R represents -CN or protected tetrazoyl group comprising the steps of reacting 2- (n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) with compound of formula (III)
  • the present invention also provides a novel compound l-[2-(l-Trityl-lH-tetrazol-5-yl-4'- methylaminocarbonyl-biphenyl ]- 1 -pentanoylamino cyclopentane of formula (IVb)
  • This compound is further cyclized to form compound of formula (V).
  • the cyclization of compound of formula (IV) is carried out by conventional manner, preferably by treating compound of formula (IV) with sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of Xylene, toluene to give compound of formula (V).
  • sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of Xylene, toluene
  • R represents cyano in compound of formula(V)
  • it is further converted to Irbesartan (I) by known method and preferably by treating with sodium azide and tributyl tin chloride or with tributyltin azide in inert solvent selected from toluene, xylene, tetrahydrofuran to give Irbesartan (I), which may be converted to its salts by conventional method.
  • IfR represents protected tetrazoyl group and preferably l-trityltetrazol-5-ly in compound of formula(V), then it is converted to Irbesartan (I) by hydrolysis.
  • Hydrolysis is carried out in presence of acid, base, alcohol or mixtures there of; preferable in presence of acid.
  • Acid can be selected from hydrochloric acid, sulfuric acid, phosphoric acid.
  • Base can be selected from NaOH, KOH, potassium tert-butoxide and the like.
  • hydrolysis can be carried out in alcohol.
  • Alcohol can be selected from methanol, ethanol, isopropanol, n- propanol, n-butanol, isobutanol, tert-butanol.
  • the preferred alcohol is methanol or ethanol. Most preferably it is carried out in presence of acid and alcohol such as hydrochloric acid and methanol.
  • the hydrolysis can be carried out in solvent such as tetrahydrofuran.
  • 2-(n ⁇ Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) is reacted with 4- aminomethyl-2'-cyanobiphenyl (Ilia) in solvent selected from hydrocarbon such as benzene, toluene, cyclohexane, hexane, xylene; ketonic solvent such as acetone, methyl ethyl ketone, MIBK; ethyl acetate, isopropyl acetate, ethers such as tetrahydrofuran, dioxane, at ambient temperature to boiling point of the solvent to form 1- (2'cyanobiphenyl-4-ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane of formula (IVa).
  • solvent selected from hydrocarbon such as benzene, toluene, cyclohexane, hexane, xylene; keto
  • the cyclization of formula (IVa) is carried out by conventional manner, preferably treating compound of formula (IVa) with sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of Xylene, toluene to give compound of formula (Va).
  • sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of Xylene, toluene to give compound of formula (Va).
  • the cyclization is preferably carried out by adding compound of formula (IVa) in toluene and further p-toluene sulfonic acid is added to the solution and heated to reflux until the completion of reaction.
  • Irbesartan (I) 2-(n-butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-l,3-diazaspiro[4,4]non-l-ene of formula (Va) is further converted to Irbesartan (I) or its salts by treating it with sodium azide and tr ⁇ butyl tinchloride or with tributyltinazide in inert solvent selected from toluene, xylene, tetrahydrofuran under reflux to form Irbesartan (I), which may be converted to its salts by conventional method.
  • compound of formula (Va) is treated with tributyltin azide in o-xylene and refluxed until the completion of reaction to form Irbesartan (I), which may be converted to its salt by conventional methods.
  • novel compound l-[2-(l-Trityl-lH-tetrazol-5-yl-4'-methyIaminocarbonyl-biphenyl]- 1 -pentanoylamino cyclopentane of formula (IVb) is further cyclized to give 2-(n-Butyl)- 3-[[2'-(l-trityl-lH-tetrazoyl-5-yl)biphenyl-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4- one (Vb).
  • the cyclization of compound (Vb) is carried out by conventional manner, preferably treating compound of formula (IVb) with sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of xylene, toluene to give compound (Vb).
  • sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of xylene, toluene to give compound (Vb).
  • the cyclization is preferably carried out by adding compound of formula (IVb) in toluene and further p- toluene sulfonic acid is added to the solution and heated to reflux until reaction is complete to obtain compound of formula (Vb), which is further hydrolyzed to
  • Hydrolysis of formula (Vb) is carried out in presence of acid, base, alcohol or mixtures thereof, preferably in presence of acid.
  • Acid can be selected from hydrochloric acid, sulfuric acid, phosphoric acid.
  • Base can be selected from NaOH, KOH, potassium tert-butoxide and the like.
  • hydrolysis can be carried out in alcohol.
  • Alcohol can be selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol.
  • the preferred alcohol is methanol or ethanol.
  • hydrolysis is carried out in presence of alcohol and acid, preferably in presence of hydrochloric acid and methanol.
  • the hydrolysis can be carried out in solvent such as tetrahydrofuran.
  • compound of formula (IVb) is hydrolyzed to give l-(2'-Tetrazole biphenyl- 4-ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane of formula (VI).
  • Hydrolysis of formula (IVb) is carried out in presence of acid, base, alcohol or mixtures thereof, preferably in presence of acid.
  • Acid can be selected from hydrochloric acid, sulfuric acid, phosphoric acid.
  • Base can be selected from NaOH, KOH, potassium tert-butoxide and the like.
  • hydrolysis can be carried out in alcohol.
  • Alcohol can be selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol.
  • the preferred alcohol is methanol or ethanol.
  • hydrolysis is carried out in presence of alcohol and acid, preferably in presence of hydrochloric acid and methanol.
  • the hydrolysis can be carried out in solvent such as tetrahydrofuran.
  • the compound of formula (VI) is further cyclized to give Irbesartan (I) or its salts. Cyclization is carried out by conventional manner, preferably treating compound of formula (VI) with sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p- toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of Xylene, toluene to give Irbesartan (I).
  • the cyclization is preferably carried out by adding compound of formula (VI) in toluene and further p-toluene sulfonic acid is added to the solution and heated to reflux until the completion of reaction.
  • Example 1 The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner. Examples: Example 1:

Abstract

The present invention relates to the novel process for the preparation of Irbesartan of formula (I) by using the 2-(n-Butyl)-3-oxa-1-azaspiro [4.4]non-1-en-4-one of formula (II) with 4-aminomethyl-2'-cyanobiphenyl of formula (IIIa).

Description

PROCESS FOR THE PREPARATION OF IRBESARTAN
FIELD OF INVENTION
The present invention relates to a novel synthesis of Irbesartan of formula (I) or its salts. Irbesartan is an angiotensin antagonists and chemically known as 2-«-butyl-4- spirocyclopentane-l-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. It is useful for the treatment of hypertension. The present invention also relates to the process for the preparation of compound of formula (V), which is useful intermediate for the preparation of Irbesartan (I)
Figure imgf000002_0001
BACKGROUND AND PRIOR ART Angiotensin II is a potent vasopressor and the biologically active product of the rennin- angiotensin system. Renin acts on the angiotensinogen of the plasma to produce angiotensin I, which is converted to angiotensin II by the action of the angiotensin I converting enzyme. Irbesartan is useful as angiotensin antagonists, particularly angiotensin-II antagonists. It inhibits the action of angiotensin II on its receptors and thus prevents the increase in blood pressure produced by the hormone receptor interaction. Thus, Irbesartan is useful for the treatment of hypertension and heart failure.
The synthesis of Irbesartan (I) has been described in US Patent no. 5,270,317. Accordingly, the process involves the reaction of 2-n-butyl-4-spirocyclopentane-2- imidazolin-5-one (A) with 4-bromomethyl-2'-cyanobiphenyl (B) in presence of base such as KOH, a metal alcoholate, a metal hydride, calcium carbonate or triethyl amine in inert solvent such as DMF, DMSO or THF to obtain 2-(n-butyl)-3-(2'cyanobiphenyl-4- ylmethyl)-4-oxo-l,3-diazaspiro[4,4]non-l-ene of formula (Va), which is a key intermediate of Irbesartan. Further, compound of formula (Va) is treated with Tributyltinazide in xylene and tritylated to give 2-(n-Butyl)-3-[[2'-(l-trityl-lH-tetrazoyl- 5-yl)biphenyl-4-yl]methyl]~l,3-diazaspiro[4.4]non-l-en-4-one of formula (Vb), which upon hydrolysis gives Irbesartan as shown in below Scheme (I).
Scheme (I)
Figure imgf000003_0001
MDC.THF
Figure imgf000003_0002
US patent no. 6,162,922 disclosed the process for the preparation of Irbesartan involving the reaction of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one (A) with 4- bromomethyl-2'-cyanobiphenyl (B) in presence of a water immiscible solvent, a base and a phase transfer catalyst to give compound of formula (Va), which is subsequently converted to Irbesartan (I).
Another synthesis approach for the preparation of Irbesartan (I) is reported in CA 2,050,769 as shown in below Scheme 2:
Figure imgf000004_0001
Accordingly, 1 -amino- l-benzyloxycarbonylcyclopentane (C) is reacted with pentanoyl chloride to form l-benzyloxycarbonyl-l-pentonylaminocyclopentane (D), which upon catalytic debenzylation with Pd/C in Methanol gives 1-carboxy-l- pentanoylaminocyclopentane (E). The compound of formula (E) is further treated with 4- aminomethyI-2'-cyanobiphenyl in presence of DCC and N-hydroxysuccinamide to give l-(2'-cyanobiphenyl-4-ylmethylaminocarbonyl)-l-pentanoylaminocycIoρentane (F), which is cyclized in presence of p-toluenesulfonic acid monohydrate in toluene to give 2- (n-butyl)-3-(2'cyanobiphenyl-4-ylmethyl)-4-oxo-l,3-diazaspiro[4,4]non-l-ene (Va) and finally converted to Irbesartan (I) with the treatment of tributyltin azide.
However, this approach involves more steps and use of costlier reagents like DCC. Also, it is low yielding. Yet another approach to prepare Irbesartan (I) is reported in US patent application pub. no. 2004/0242894 Al as shown in below Scheme 3:
Figure imgf000005_0001
(I) (Vb)
Accordingly, reaction of (2-(l-trityl-lH-tetrazol-5-yl)-4'-aminomethylbiphenyl (HIb) with ethyl valerimidate methanesulfonic acid salt gives N-valerimidate 5' - (4'- aminomethyl biphenyl-2-yl)-ltrityI-lH-tetrazoI (G), which upon reaction with 1-amino cyclopentane carboxylic acid ethyl ester to give 2-n-Butyl-3-[[2'-(l-trityl-lH-tetrazoyl-5- yl)biphenyl-4-yl]methyl]-l,3-diazaspiro[4,4]non-l-en-4-one(Vb). This compound (Vb) is converted to Irbesartan (I) by conventional methods. However, this approach of the synthesis of Irbesartan (I) is low yielding (about 20%) and requires purification by column chromatography, which is laborious and costlier and not feasible at commercial scale.
OBJECTS OF INVENTION
The object of the present invention is to provide a novel process for the preparation of Irbesartan. The further object of the invention is to provide a novel process for the preparation of compound formula (V), which is an important intermediate for the preparation of Irbesartan (I).
Still another object of the invention is to a provide novel compound 1 -[2-( 1 -Trityl- 1 H- tetrazol-5 -yl-4 ' -methylaminocarbonyl-biphenyl] - 1 -pentanoylamino cyclopentane of formula (IVb)
In summary, the object of the present invention is to provide a novel process for the preparation of Irbesartan and its intermediate, which is simple and easy to handle and cost effective.
SUMMARY OF INVENTION
According to one aspect the present invention provides a novel process for the preparation of Irbesartan of formula (I) or its salts, which comprises
Figure imgf000006_0001
reacting 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) with compound of formula (III)
Figure imgf000006_0002
wherein R represents -CN, protected tetrazoly group; to give compound of formula (IV) and cyclizing the compound of formula (IV) to obtain compound of formula (V)
Figure imgf000007_0001
wherein R is as described above, and converting it to Irbesartan of formula (I) or its salts. The present invention also provides a novel process for the preparation of Irbesartan of formula (I) or its salts comprising the steps of
Figure imgf000007_0002
(a) reacting 2-(n-Butyl)-3-oxa-l-azasρiro [4.4]non-l-en-4-one of formula (II) with 4- aminomethyl-2'-cyanobiphenyl of formula (Ilia)
Figure imgf000007_0003
to give l-(2'-cyanobiphenyl-4-ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane formula (IVa)
Figure imgf000007_0004
(b) cyclizing the compound of formula (IVa) to give 2-(n-butyl)-3-(2'cyanobiphenyl-4- ylmethyl)-4-oxo-l,3-diazaspiro[4,4]non-l-ene of formula (Va)
Figure imgf000008_0001
(c) converting the compound for formula (Va) to Irbesartan of formula (I) or its salts
According to another aspect the present invention provides a process for the preparation of Irbesartan of formula (I) or its salts comprising the steps of
Figure imgf000008_0002
(a) reacting 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) with 2-(l- trityl-lH-tetrazol-5-yl)-4'-aminomethylbiphenyl of formula (HIb)
Figure imgf000008_0003
to give novel compound l-[2-(l-Trityl-lH-tetrazol-5-yl-4'-methylaminocarbonyl- biphenyl]-l-pentanoylamino cyclopentane of formula (IVb)
Figure imgf000008_0004
(b) cyclizing the compound of formula (IVb) to give 2-(n-Butyl)-3-[[2'-(l-trityl-lH- tetrazoyl-5-yl)biphenyl-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4-one of formula (Vb)
Figure imgf000009_0001
(c) converting the compound for formula (Vb) to Irbesartan of formula (I) or its salts
According to a further aspect the present invention, provides a further process for the preparation of Irbesartan (I) or its salts comprises the steps of
(a) reacting 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) with (2-(l- trityl-lH-tetrazol-5-yl)-4'-ammomethylbiphenyI of formula (IEEb)
Figure imgf000009_0002
to give novel compound l-[2~(l-Trityl-lH-tetrazol-5-yl-4'-methylaminocarbonyl- biphenyl]-l-pentanoylamino cyclopentane of formula (IVb)
Figure imgf000009_0003
(b) hydrolyzing the compound of formula (IVb) to give l-(2'-Tetrazol-5-yl-biphenyl-4- ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane of formula (VI)
Figure imgf000010_0001
(c) cyclizing the compound of formula (VI) to give Irbesartan of formula (I) or its salts
The present invention also provides a novel process for the preparation of the compound of formula (V),
Figure imgf000010_0002
wherein R represents -CN or protected tetrazoyl group comprising the steps of reacting 2- (n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) with compound of formula (III)
Figure imgf000010_0003
wherein R is as defined above to give compound of formula (IV) and cyclizing the said compound of formula (IV).
The present invention also provides a novel compound l-[2-(l-Trityl-lH-tetrazol-5-yl-4'- methylaminocarbonyl-biphenyl ]- 1 -pentanoylamino cyclopentane of formula (IVb)
Figure imgf000011_0001
DETAILED DESCRIPTION OF INVENTION
The synthesis of Irbesartan (I) or its salts by reaction of 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) with compound of formula (III) in solvent selected from hydrocarbon such as benzene, toluene, cyclohexane, hexane, xylene; ketonic solvent such as acetone, methyl ethyl ketone, MIBK; ethyl acetate, isopropyl acetate, ethers such as tetrahydrofuran, dioxane, at ambient temperature to boiling point of the solvent to form the compound of formula (IV). This compound is further cyclized to form compound of formula (V). The cyclization of compound of formula (IV) is carried out by conventional manner, preferably by treating compound of formula (IV) with sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of Xylene, toluene to give compound of formula (V).
If R represents cyano in compound of formula(V), then it is further converted to Irbesartan (I) by known method and preferably by treating with sodium azide and tributyl tin chloride or with tributyltin azide in inert solvent selected from toluene, xylene, tetrahydrofuran to give Irbesartan (I), which may be converted to its salts by conventional method.
IfR represents protected tetrazoyl group and preferably l-trityltetrazol-5-ly in compound of formula(V), then it is converted to Irbesartan (I) by hydrolysis. Hydrolysis is carried out in presence of acid, base, alcohol or mixtures there of; preferable in presence of acid. Acid can be selected from hydrochloric acid, sulfuric acid, phosphoric acid. Base can be selected from NaOH, KOH, potassium tert-butoxide and the like. Also, hydrolysis can be carried out in alcohol. Alcohol can be selected from methanol, ethanol, isopropanol, n- propanol, n-butanol, isobutanol, tert-butanol. The preferred alcohol is methanol or ethanol. Most preferably it is carried out in presence of acid and alcohol such as hydrochloric acid and methanol. The hydrolysis can be carried out in solvent such as tetrahydrofuran.
In accordance with the present invention for the preparation of Irbesartan (I) or its salts, 2-(n~Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) is reacted with 4- aminomethyl-2'-cyanobiphenyl (Ilia) in solvent selected from hydrocarbon such as benzene, toluene, cyclohexane, hexane, xylene; ketonic solvent such as acetone, methyl ethyl ketone, MIBK; ethyl acetate, isopropyl acetate, ethers such as tetrahydrofuran, dioxane, at ambient temperature to boiling point of the solvent to form 1- (2'cyanobiphenyl-4-ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane of formula (IVa). The reaction is preferably carried out in toluene or tetrahydrofuran, more preferably in toluene at ambient temperature to 5O0C and preferably at ambient temperature.
1 -(2'-cyanobiρhenyl-4-ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane of formula (IVa) is further cyclized to give 2-(n-butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4- oxo-l,3-diazaspiro[4,4]non-l-ene of formula (Va). The cyclization of formula (IVa) is carried out by conventional manner, preferably treating compound of formula (IVa) with sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of Xylene, toluene to give compound of formula (Va). The cyclization is preferably carried out by adding compound of formula (IVa) in toluene and further p-toluene sulfonic acid is added to the solution and heated to reflux until the completion of reaction.
2-(n-butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-l,3-diazaspiro[4,4]non-l-ene of formula (Va) is further converted to Irbesartan (I) or its salts by treating it with sodium azide and trϊbutyl tinchloride or with tributyltinazide in inert solvent selected from toluene, xylene, tetrahydrofuran under reflux to form Irbesartan (I), which may be converted to its salts by conventional method. Preferably, compound of formula (Va) is treated with tributyltin azide in o-xylene and refluxed until the completion of reaction to form Irbesartan (I), which may be converted to its salt by conventional methods.
In accordance with the present invention for the alternative process for the preparation of Irbesartan (I) or its salts, 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) is reacted with 2-(l-trityl-lH-tetrazoyl-5-yI)-4'-aminomethylbiphenyl of formula (HIb) in solvent selected from hydrocarbon such as benzene, toluene, cyclohexane, hexane, xylene; ketonic solvent such as acetone, methyl ethyl ketone, MIBK; ethyl acetate, isopropyl acetate, ethers such as tetrahydrofuran, dioxane, at ambient temperature to boiling point of the solvent to form novel compound l-[2-(l-Trityl-lH- tetrazol-5-yl-4' -methylaminocarbonyl-biphenyl]- 1 -pentanoylamino cyclopentane of formula (IVb). The reaction is preferably carried out in toluene or tetrahydrofuran, more preferably in toluene at ambient temperature to 5O0C and preferably at ambient temperature.
The novel compound l-[2-(l-Trityl-lH-tetrazol-5-yl-4'-methyIaminocarbonyl-biphenyl]- 1 -pentanoylamino cyclopentane of formula (IVb) is further cyclized to give 2-(n-Butyl)- 3-[[2'-(l-trityl-lH-tetrazoyl-5-yl)biphenyl-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4- one (Vb).
The cyclization of compound (Vb) is carried out by conventional manner, preferably treating compound of formula (IVb) with sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of xylene, toluene to give compound (Vb). The cyclization is preferably carried out by adding compound of formula (IVb) in toluene and further p- toluene sulfonic acid is added to the solution and heated to reflux until reaction is complete to obtain compound of formula (Vb), which is further hydrolyzed to give Irbesartan (I) or its salts. Hydrolysis of formula (Vb) is carried out in presence of acid, base, alcohol or mixtures thereof, preferably in presence of acid. Acid can be selected from hydrochloric acid, sulfuric acid, phosphoric acid. Base can be selected from NaOH, KOH, potassium tert-butoxide and the like. Also, hydrolysis can be carried out in alcohol. Alcohol can be selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol. The preferred alcohol is methanol or ethanol. Preferably, hydrolysis is carried out in presence of alcohol and acid, preferably in presence of hydrochloric acid and methanol. The hydrolysis can be carried out in solvent such as tetrahydrofuran.
Alternatively, compound of formula (IVb) is hydrolyzed to give l-(2'-Tetrazole biphenyl- 4-ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane of formula (VI). Hydrolysis of formula (IVb) is carried out in presence of acid, base, alcohol or mixtures thereof, preferably in presence of acid. Acid can be selected from hydrochloric acid, sulfuric acid, phosphoric acid. Base can be selected from NaOH, KOH, potassium tert-butoxide and the like. Also, hydrolysis can be carried out in alcohol. Alcohol can be selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol. The preferred alcohol is methanol or ethanol. Preferably, hydrolysis is carried out in presence of alcohol and acid, preferably in presence of hydrochloric acid and methanol. The hydrolysis can be carried out in solvent such as tetrahydrofuran.
The compound of formula (VI) is further cyclized to give Irbesartan (I) or its salts. Cyclization is carried out by conventional manner, preferably treating compound of formula (VI) with sulfonic acid such as methane sulfonic acid, ethane sulfonic acid, p- toluene sulfonic acid or with sulfuric acid in inert solvent selected from group comprising of Xylene, toluene to give Irbesartan (I). The cyclization is preferably carried out by adding compound of formula (VI) in toluene and further p-toluene sulfonic acid is added to the solution and heated to reflux until the completion of reaction.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner. Examples: Example 1:
Preparation of l-(2'-cyanobiphenyl-4-ylmethylaminocarbonyl)-l -pentanoylamino cyclopentane (IVa)
In a 3 necked 0.5 liter round bottom flask equipped with mechanical stirrer, was charged with 4-aminomethyl-2'-cyanobiphenyl (21.5 g; 0.103 mole) and toluene (160 ml) and stirred to get clear solution. 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one (20 g; 0.103 moles) was added in one portion and stirred it for 2 hours at ambient temperature. The product was precipitated out. The product was filtered and washed with toluene (20mlx2). The product was dried under vacuum at 6O0C for 4 hours.(Yield : 37g; 89%)
IH-NMR (CDC13) : δppm 0.89 (t,3H); 1.24-137(sex,2H); 1.53-1.63(quent,2H);
1.74- 1.81(m,4H); 1.91 (s, IH) ; 1.98-2.04 (m, 2H) ; 2.19(t, 2H) ; 2.29-2.36 (m, 2H) ; 4.5(d,2H); 5.9(s,lH);
7.37-7.77 (m, 8H) M+ : 404.6
Example 2: Preparation of 2-( n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-l,3 diazaspiro [4.4] non-1 -ene (Va)
In a 3 necked 1 liter round bottom flask equipped with mechanical stirrer, was charged with l-(2'-cyanobiphenyl-4-ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane (17.0 g; 0.042 mole), toluene (340 ml) and para-toluene sulfonic acid (8.8 g; 0.047 mole) and stir it. The reaction mixture was heated to reflux under stirring for 24 hours and water was separated by dean & stark condenser. The reaction mixture was cooled to ambient temperature and water (200ml ) was added and stirred for 10 minutes. The phases were separated and organic phase was washed with water (100ml) and brine (100ml). The organic phase was dried over sodium sulphate and toluene was distilled out under reduced pressure. The residue was stirred with methyl tert-butyl ether (15ml) for 2 hours. The product was filtered and washed with methyl isobutyl ether. The product was dried under vacuum at 60oC. (Yield : 7.6g; 46.7%)
IH-NMR (CDCI3) : δppm 0.88 (t,3H); 1.27-140(sex,2H); 1.54-1.64(quent,2H);
1.82- 2.07(m,10H); 2.35(t, 2H) ; 4.74(s, 2H) ; 7.26-7.7(m, 8H) M+ : 386.6.
Example 3:
Preparation of Irbesartan (I)
In a 3 necked 1 liter round bottom flask equipped with mechanical stirrer, was charged with 2-( n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-l,3 diazaspiro [4.4] non-1-ene (18.5.0 g; 0.048 mole), o-xylene (250 ml) and tributyltin azide (28 g; 0.084 mole) and stirred it. The reaction mixture was heated to reflux under stirring for 80 hours. The reaction mixture was cooled to ambient temperature and IN sodium hydroxide (200ml ) was added and stirred for 30 minutes. The phases were separated and aqueous phase was washed with o-xylene (100ml) and isopropyl ether (100ml). The aqueous phase was treated with activated charcoal and filtered through hyflo bed. The filtrate was cooled to 0 to 1O0C and pH was adjusted to 4.6 by 3N hydrochloric acid on pH meter. The product was filtered, washed with water, dried under vacuum at 6O0C add crystallized in rectified spirit. (Yield : 16g; 78%)
IH-NMR (DMSO d6) : δppm 0.78 (t,3H); 1.17-130(sex,2H); 1.40-1.50(quent,2H); 1.64-
1.67 (m,2H); 1.80-1.82(m, 6H); 2.27(t,2H) ; 4.67(s, 2H) ; 7.07(s, 4H);7.51-7.68(m,4H) M+ : 429.6 Example 4:
Preparation of 1 -[2-(I -Trityl-lH-tetrazol-5-yl-4' -methylaminocarbonyl-biphenyl]- 1 - pentanoylamino cyclopentane (IVb)
In a 3 necked 1.0 liter round bottom flask equipped with mechanical stirrer, was charged with (2-(l-trityI-lH-tetrazol-5-yl)-4'-aminomethylbiphenyl (50.5 g; 0.102 mole) and toluene (750 ml) and stirred to get clear solution. 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non- l-en-4-one (20 g; 0.102 mole) was added in one portion and stirred for 2 hours at ambient temperature. The product was precipitated out. The product was filtered and washed with toluene (25mlx2). The product was dried under vacuum at 6O0C for 4 hours.(Yield : 62g; 88%)
IH-NMR (CDC13) : δppm 0.87 (t,3H); 1.22-132(sex,2H); 1.53-1.58(quent,2H); 1.72-
1.76(m,4H); 1.90-1.02(m, 4H); 2.13(t,2H) ; 2.25-2.32(m, 2H); 2.35(s,2H); 4.33(d, 2H) ; 6.89-7.89(m,23H) M+ : 689.8
Example 5:
Preparation of l-(2'-Tetrazole biphenyl-4-yImethylaminocarbonyl)-l-pentanoylamino cyclopentane (VI)
In a 3 necked 0.5 liter round bottom flask equipped with mechanical stirrer, was charged with l-(2'-trityltetrazole biphenyl-4-ylmethylarninocarbonyl)-l-pentanoylamino cyclopentane (9.0 g; 0.13 mole) , methanol (45.0 ml) and tetrahydrofuran (45.0 ml) and stirred to get clear solution. The reaction mass was chilled to 0-50C and add drop wise 5N hydrochloric acid (9.0ml). The reaction mixture was allowed to attain at ambient temperature and stirred overnight. The progress of the reaction was monitored by thin layer chromatography. Methanol and tetrahydrofuran was distilled out under vacuum. The residue was extracted with toluene (90ml) and IN sodium hydroxide (120ml). The two phases were separated and aqueous phase was washed with isopropyl ether (50ml). The aqueous phase was adjusted to pH 2 by 3N hydrochloric acid. The product was filtered and washed with water and dry it in air.(Yield : 5.5g; 94%) Example 6:
Preparation of Irbesartan
In a 3 necked 1 liter round bottom flask equipped with mechanical stirrer, was charged with l-(2'-Tetrazole biphenyl-4-ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane (2 g; 0.0048 mole), toluene (20 ml) , p toluenesulfonic acid (1.7 g; 0.0089 mole) and dimethylformamide (5 ml) and stirred. The reaction mixture was heated to reflux using dean and stark water separator under stirring for 30 hours. The reaction mixture was cooled to ambient temperature and IN sodium hydroxide (50ml ) was added and stirred for 30 minutes. The phases were separated and aqueous phase was washed with isopropyl ether (10ml). The aqueous phase was treated with activated charcoal and filtered through hyflo bed. The filtrate was cooled 1O0C and pH was adjusted to 4.6 by 3N hydrochloric acid on pH meter. The product was filtered, washed with water, dried under vacuum at 60oC. (Yield: 1.Og; 52%)
Example 7:
Preparation of 2-(n-Butyl)-3-[[2'-(l-trityl-lH-tetrazoyl-5-yl)biphenyl-4-yl]methyl]-l,3- diazaspiro[4.4]non-l-en-4-one (Vb)
In a 3 necked 1 litre round bottom flask equipped with mechanical stirrer, was charged with 1 - [2-( 1 -Tr ityl- 1 H-tetrazol-5 -yl-4 ' -methylaminocarbony l~bipheny I]- 1 - pentanoylamino cyclopentane (17.6 g; 0.025 mole), toluene (190 ml) , methane sulfonic acid (1.8 ml; 0.028 mole) and stir it. The reaction mixture was heated to reflux using dean and stark water separator under stirring for 21 hours. The reaction mixture was cooled to ambient temperature and washed with water and brine. Toluene was distilled out under vacuum to obtain crude 2-Butyl-3{[2'-(l-trityl-lH-tetrazol-5-yl)l,l'-biphenyl]-4- yl]methyl}-l,3-diazaspiro[4,4]non-l-en-4-one as oil. (Yield: 11.5g )
Example 8:
Preparation of Irbesartan (I)
In a 3 necked 0.5 litre round bottom flask equipped with mechanical stirrer, was charged with 2-(n-ButyI)-3-[[2'-(l -trityl- 1 H-tetrazoyl-5-yl)biphenyl-4-yl]methylJ-l ,3- diazaspiro[4.4]non-l-en-4-one (11.5 g) , methanol (57.0 ml) and tetrahydrofuran (57.0 ml) and stirred to get clear solution. The reaction mass was chilled to 0-50C and add drop wise 5N hydrochloric acid (11.5ml). The reaction mixture was allowed to attain at ambient temperature and stirred overnight. The progress of the reaction was monitored by thin layer chromatography. Methanol and tetrahydrofuran was distilled out under vacuum. The residue was portioned between toluene (90ml) and IN sodium hydroxide (115ml). The two phases were separated and aqueous phase was washed with isopropyl ether (50ml). The aqueous phase was adjusted to pH 4.6 by 3N hydrochloric acid. The product was filtered and washed with water and dry it in air.
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 novel process for the preparation of Irbesartan of formula (I) or its salts comprising
Figure imgf000020_0001
reacting 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) with compound of formula (III)
Figure imgf000020_0002
wherein R represents -CN, protected tetrazoly group; to give compound of formula (IV) and cyclizing the compound of formula (IV) to obtain compound of formula (V)
Figure imgf000020_0003
wherein R is as defined above and converting to Irbesartan of formula (I) or its salts.
2. A novel process for the preparation of Irbesartan of formula (I) or its salts comprising the steps of
Figure imgf000020_0004
(a) reacting 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) with 4- aminomethyl-2'-cyanobiphenyl of formula (Ilia)
Figure imgf000021_0001
to give l-(2'-cyanobiphenyl-4-ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane formula (IVa)
Figure imgf000021_0002
(b) cyclizing the compound of formula (IVa) to give 2-(n-butyl)-3-(2'-cyanobiρhenyl-4- ylmethyl)-4-oxo-l,3-diazaspiro[4,4]non-l-ene of formula (Va)
Figure imgf000021_0003
(Va)
(c) converting the compound for formula (Va) to Irbesartan of formula (I) or its salts
3. A novel process for the preparation of Irbesartan of formula (I) or its salts comprising the steps of
Figure imgf000021_0004
(a) reacting 2-(n-Butyl)-3-oxa-l-azaspiro [4.4Jnon-l-en-4-one of formula (II) with (2-(l- trityl-lH-tetrazol-5-yl)-4'-aminomethylbiphenyl of formula (HIb)
Figure imgf000022_0001
to give novel compound l-[2-(l-Trityl-lH-tetrazol-5-yl-4'-methylaminocarbonyl- biphenyl]-l-pentanoylamino cyclopentane of formula (IVb)
Figure imgf000022_0002
(b) cyclizing the compound of formula (IVb) to give 2-(n-Butyl)-3-[[2'-(l-trityl-lH- tetrazoyl-5-yl)biphenyl-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4-one of formula (Vb)
Figure imgf000022_0003
(c) converting the compound for formula (Vb) to Irbesartan of formula (I) or its salts
4. A process for the preparation of Irbesartan (I) or its salts comprises the steps of
(a) reacting 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) with (2-(l- trityl- lH-tetrazol-5-yl)-4'-aminomethylbiphenyl of formula (Mb)
Figure imgf000022_0004
to give novel compound l-[2-(l-Trityl-lH-tetrazol-5-yl-4'-methylaminocarbonyl- biphenyl]-l-pentanoylamino cyclopentane of formula (IVb)
Figure imgf000023_0001
(b) hydrolyzing the compound of formula (IVb) to give l-(2'-Tetrazole bipHenyl-4- ylmethylaminocarbonyl)-l-pentanoylamino cyclopentane of formula (VI)
Figure imgf000023_0002
(c) cyclizing the compound of formula (VI) to give Irbesartan of formula (I) or its salts
5. A novel process for the preparation of the compound of formula (V),
Figure imgf000023_0003
wherein R represents -CN or protected tetrazoyl group, comprising reaction of 2-(n- Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) with compound of formula (III)
Figure imgf000023_0004
wherein R is as defined above to give compound of formula (IV) and cyclizing the said compound of formula (IV).
6. A process according to claim 1, 2, 3, 4 or 5, wherein cyclization is carried out in presence of sulfonic acid selected from methane sulfonic acid, ethane sulfonic acid, p- toluene sulfonic acid or with sulfuric acid, preferably in presence of para-toluene sulfonic acid.
7. A process according to claim 1, 2, 3, 4 or 5, wherein hydrolysis is carried out in presence of acid, base, alcohol or mixtures thereof.
8. A process according to claim 7, wherein said acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid; said base is selected from NaOH, KOH, potassium tert- butoxide; said alcohols is selected from methanol, ethanol, isopropanol, n-propanol, n- butanol, isobutanol, tert-butanol.
9. A novel compound l-[2-(l-Trityl-lH-tetrazol-5-yl-4'-methylaminocarbonyl-biphenyl]- 1-pentanoylamino cyclopentane of formula (IVb)
Figure imgf000024_0001
10. Use of compound of 2-(n-Butyl)-3-oxa-l-azaspiro [4.4]non-l-en-4-one of formula (II) in the preparation of Irbesartan (I) or its salts.
11. A process for the preparation of Irbesartan (I) or its salts such as herein described and illustrated in the examples.
PCT/IN2006/000323 2005-08-31 2006-08-28 Process for the preparation of irbesartan WO2007052301A2 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2036904A1 (en) * 2007-08-08 2009-03-18 LEK Pharmaceuticals D.D. A process for the preparation of olmesartan medoxomil
EP2194050A1 (en) 2008-12-08 2010-06-09 KRKA, tovarna zdravil, d.d., Novo mesto A new process for the preparation of irbesartan
US8592474B2 (en) 2007-08-08 2013-11-26 Lek Pharmaceuticals D.D. Process for the preparation or purification of olmesartan medoxomil
CN103787999A (en) * 2013-12-18 2014-05-14 吉林修正药业新药开发有限公司 Synthesis method of irbesartan impurity
CN107235963A (en) * 2017-08-07 2017-10-10 南京普氟生物检测技术有限公司 A kind of method for efficiently preparing Irbesartan impurity A

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0475898A1 (en) * 1990-09-10 1992-03-18 Ciba-Geigy Ag Azacyclic compounds
US20040242894A1 (en) * 2003-02-05 2004-12-02 Ben-Zion Dolitzky Novel synthesis of 2-butyl-3-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspiro[4.4]-non-ene-4-one
WO2005051943A1 (en) * 2003-11-28 2005-06-09 Ranbaxy Laboratories Limited Processes for the preparation of highly pure irbesartan
EP1749828A1 (en) * 2005-08-04 2007-02-07 Farmaprojects S.L. Process for preparing an angiotensin II receptor antagonist

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0475898A1 (en) * 1990-09-10 1992-03-18 Ciba-Geigy Ag Azacyclic compounds
US20040242894A1 (en) * 2003-02-05 2004-12-02 Ben-Zion Dolitzky Novel synthesis of 2-butyl-3-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)-1,3-diazaspiro[4.4]-non-ene-4-one
WO2005051943A1 (en) * 2003-11-28 2005-06-09 Ranbaxy Laboratories Limited Processes for the preparation of highly pure irbesartan
EP1749828A1 (en) * 2005-08-04 2007-02-07 Farmaprojects S.L. Process for preparing an angiotensin II receptor antagonist

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2036904A1 (en) * 2007-08-08 2009-03-18 LEK Pharmaceuticals D.D. A process for the preparation of olmesartan medoxomil
US8592474B2 (en) 2007-08-08 2013-11-26 Lek Pharmaceuticals D.D. Process for the preparation or purification of olmesartan medoxomil
EP2194050A1 (en) 2008-12-08 2010-06-09 KRKA, tovarna zdravil, d.d., Novo mesto A new process for the preparation of irbesartan
CN103787999A (en) * 2013-12-18 2014-05-14 吉林修正药业新药开发有限公司 Synthesis method of irbesartan impurity
CN107235963A (en) * 2017-08-07 2017-10-10 南京普氟生物检测技术有限公司 A kind of method for efficiently preparing Irbesartan impurity A

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