WO2007054965A2 - Process for preparation of tetrazoles from aromatic cyano derivatives - Google Patents

Process for preparation of tetrazoles from aromatic cyano derivatives Download PDF

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WO2007054965A2
WO2007054965A2 PCT/IN2006/000346 IN2006000346W WO2007054965A2 WO 2007054965 A2 WO2007054965 A2 WO 2007054965A2 IN 2006000346 W IN2006000346 W IN 2006000346W WO 2007054965 A2 WO2007054965 A2 WO 2007054965A2
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WO2007054965A3 (en
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Pandurang Balwant Deshpande
Parvenkumar Luthra
Anandkumar Pandey
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Alembic Ltd
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    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to process for preparation of tetrazoles of formula (I) from aromatic cyano derivatives of formula (II) comprising of treating the cyano compound of formula (II) with trialkyltin halide and metal azide in presence of base.
  • This process is useful for preparation of various compounds belonging to the class of non-peptide angiotensin-II inhibitors such as Valsartan of formula (A), Candesartan of formula (B), Irbesartan of formula (C), Losartan of formula (D), Olmesartan of formula (E) and Tasosartan of formula (F).
  • Valsartan of formula (A), Candesartan of formula (B), Irbesartan of formula (C), Losartan of formula (D), Olmesartan of formula (E) and Tasosartan of formula (F) are angiotensin II receptor antagonists also known as angiotensin receptor blockers (ARBs) and are useful for the treatment of hypertension and congestive heart failure. They act by inhibiting the action of angiotensin II on its receptors and prevent the increase in blood pressure produced by hormone-receptor interactions. These compounds contain a common structural feature - the 5-tetrazole group.
  • Valsartan of formula (A), Candesartan of formula (B), Irbesartan of formula (C), Losartan of formula (D), Olmesartan of formula (E) and Tasosartan of formula (F) are reported in US Patent No. 5,399,578, US Patent No. 5,196,444, US Patent No. 5,270,317, US Patent No. 5,138,069, US patent No. 5,616,599 and US Patent No. 5.149,699 respectively.
  • the route commonly followed for obtaining the 5-tetrazole moiety in the desired compound is by carrying out cyclization of the corresponding cyano derivative in presence of organo- tin azides. These compounds are purified by column chromatography and if desired further recrystalization can be carried out. But these processes generally suffer by giving low yields, longer reaction times and final purification by tedious chromatographic techniques.
  • the object of the present invention to provide a process of preparation of tetrazole of formula (I) from aromatic cyano derivatives of formula (II) which is high yielding, has shorter reaction times and gives desired compound with high purity.
  • Another object of the invention is to provide a process for preparing Valsartan, Candesartan, Irbesartan, Losartan, Olmesartan or Tesosartan, which is simple, easy to handle and cost effective.
  • R is selected from group comprising of formula (a), (b), (c), (d) or (e)
  • R is independently selected from hydrogen, C 1-6 alkyl, -CN, -NO 2 , -COOH, -COOCi -6 alkyl, -COORa (wherein Ra is benzyl, Ci -6 alkanoyloxy Ci -6 alkyl, C 6-7 cycloalkanoyloxy C ]-6 alkyl, Ci -6 alkoxycarbonyloxy Ci -6 alkyl, C 5-6 cycloalkoxycarbonyloxy Ci -6 alkyl, (5-phenyl-2-oxo- l,3-dioxolen-4-yl)methyl group, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl group, (5- ethyl-2-oxo
  • Valsartan or a stereoisomer or a precursor thereof comprising reacting compounds of formula (Hd) with trialkyltin halide and metal azide in presence of base
  • Rx represents hydrogen, Ci-C 6 alkyl selected from methyl, ethyl, n-propyl, iso- propyl, n-butyl, tert-butyl, 2-methyl-propyl or benzyl to give Valsartan or a stereoisomer or a salt thereof.
  • Yet another embodiment of the present invention provides a process of preparing Candesartan or a stereoisomer or a ester or a precursor thereof comprising reacting compounds of formula (lib) with trialkyltin halide and metal azide in presence of base
  • Ry represents -COOH and salts thereof, -COOMe, -COOEt, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, 1 -(cyclohexyloxycarbonyloxy)ethoxycarbonyl, 5-methyl- 2-oxo-l,3-dioxolen-4-ylmethyloxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxy-carbonyl, isobutyryloxymethoxycarbonyl, l-(ethoxycarbonyloxy)ethoxycarbonyl, l-(acetyloxy)ethoxycarbonyl, l-(isobutyryloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbony
  • a process of preparing Irbesartan or a stereoisomer or a precursor thereof comprising reacting compounds of formula (Ha) with trialkyltin halide and metal azide in presence of base to give Irbesartan or a stereoisomer or a salt thereof.
  • a process of preparing Losartan or a stereoisomer or a precursor thereof comprising reacting compounds of formula (lie) with trialkyltin halide and metal azide in presence of base to give Losartan or a stereoisomer or a salt thereof.
  • a process of preparing Olmesartan or a stereoisomer or a precursor thereof comprising reacting compounds of formula (Hc') with trialkyltin halide and metal azide in presence of base to give Olmesartan or a stereoisomer or a salt thereof.
  • a process of preparing Tasosartan or a stereoisomer or a precursor thereof comprising reacting compounds of formula (He) with trialkyltin halide and metal azide in presence of base to give Tasosartan or a stereoisomer or a salt thereof.
  • R is selected from group comprising of formula (a), (b), (c), (d) or (e)
  • R 1 , R 2 , R3, R 4 , R5, R 6 , R7, Rs and R9 are independently selected from hydrogen, Ci -6 alkyl, -CN, -NO 2 , -COOH, -COOCi -6 alkyl, -COORa (wherein Ra is benzyl, Ci -6 alkanoyloxy Ci -6 alkyl, C 6-7 cycloalkanoyloxy Ci -6 alkyl, Ci -6 alkoxycarbonyloxy Ci -6 alkyl, C 5-6 cycloalkoxycarbonyloxy Ci -6 alkyl, (5-phenyl-2-oxo- l,3-dioxolen-4-yl)methyl group, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl group, (5- ethyl-2-oxo
  • the reaction can be carried out in presence of suitable solvent selected from the group comprising of aliphatic, cycloaliphatic and aromatic hydrocarbon, such as an C5-C 1 0 alkane e. g. heptane, a cycloalkane such as cyclohexane ; an alkylated C 3 -C 7 cycloalkane such as methyl-cyclohexane or 1, 3-dimethyl-cyclohexane, an alkylated benzene such as ethylbenzene, toluene, xylene, cumene, or mesitylene ; a halogenated aromatic solvent such as chlorobenzene, o-, m- or p-chlorotoluene, dichlorobenzene, and trifluoromethylbenzene which may be further substituted e.g.
  • suitable solvent selected from the group comprising of aliphatic, cycloaliphatic and aromatic hydrocarbon, such as
  • C 1 -C 7 alkyl or C 1 -C 7 alkoxy by C 1 -C 7 alkyl or C 1 -C 7 alkoxy; an halogenated hydrocarbon like such as methylenedichloride, ethylenedichloride or chloroform; a halogenated aromatic compound, such as chlorobenzene; an ether, such as tetrahydrofuran, diisoproyl ether; an ketone, such as diisobutyl ketone, methyl isobutyl ketone; high boiling aprotic solvents such as dioxane, dimethylformamide, dimethylacetamide, dimethylsulphoxide; or mixtures thereof.
  • an halogenated hydrocarbon like such as methylenedichloride, ethylenedichloride or chloroform
  • a halogenated aromatic compound such as chlorobenzene
  • an ether such as tetrahydrofuran, diisoproyl ether
  • an ketone such as
  • the reaction is carried out at temperature ranging from about 0 0 C to about reflux temperature of the solvent, more preferably at about 2O 0 C to about 250 0 C.
  • the reaction time varies from about 1 hour to about 150 hours, more preferably from about 10 hours to about 50 hours.
  • the trialkyltin halide can be trialkyltin chloride selected from group of trimethyltin chloride, triethyltinchloride, tributyltinchloride and like.
  • the metal azide can be selected from inorganic azide like sodium, potassium or lithium azide.
  • the base is a nitrogeneous base selected form group of primary, secondary or tertiary amines for e.g. isopropyl amine, diethyl amine, triethyl amine, tributyl amine, diisopropyl ethyl amine and like.
  • 5-tetrazole protected compound protected with suitable protecting group selected from trityl, monomethyoxytrityl, dimethoxytrityl, benzhydryl, acyl, benzyl which is unsubstituted or substituted, for example by nitro, such as 4- nitrobenzyl, lower alkoxymethyl, such as methoxy- and ethoxymethyl, lower alkylthiomethyl, such as methylthiomethyl, silyl, such as tri-lower alkylsilyl, for example dimethyl-tert-butyl- and triisopropylsilyl, and 2-cyanoethyl, also lower alkoxy-lower alkoxymethyl, such as 2-methoxyethoxymethyl, benzyloxymethyl, phenacyl or like by process known to person skilled in general art.
  • suitable protecting group selected from trityl, monomethyoxytrityl, dimethoxytrityl, benzhydryl, acyl,
  • process for the preparation of Valsartan of formula (A) or a stereoisomer or a precursor thereof comprises treating compound of formula (II)
  • Rx represents -H, C]-C 6 alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, 2-methyl-propyl or benzyl.
  • reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
  • Ry represents -COOH and salts thereof, -COOMe, -COOEt, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, l-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, 5-methyl- 2-oxo-l,3-dioxolen-4-ylmethyloxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxy-carbonyl, isobutyryloxymethoxycarbonyl, l-(ethoxycarbonyloxy)ethoxycarbonyl, 1 -(acetyloxy)ethoxycarbonyl, 1 -(isobutyryloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbony
  • reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
  • reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
  • reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
  • reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
  • reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
  • the mixture was filtered through hyflo bed and the phases were separated and aqueous phase was washed with o- xylene and isopropyl ether.
  • the aqueous phase was treated with activated charcoal and filtered through hyflo bed.
  • the filtrate was cooled 5-1O 0 C and pH was adjusted to 4-5 by 3N hydrochloric acid on pH meter.
  • the product was filtered, washed, dried under vacuum at 6O 0 C and crystallized in rectified spirit.
  • N-[(2'-cyanobiphenyl-4yl)methyl]-N-pentanoyl-(L)-valine methyl ester obtained in step (a) tri n.butyltin chloride (60.1 g), sodium azide (11.85g) and triethylamine (2.5g) was refluxed for 8-12 hours.
  • reaction mixture was distilled at reduced pressure and remaining product dissolved by alcohol (20 ml). Then (6M, 10 ml) HCl is added and extract with ethyl acetate (2 X 30 ml) and combine organic layer and wash it with water. Distilled out organic layer and residue dissolve in alcohol (15 ml) and water (5 ml) and stir for 7 hour at 2O 0 C to 3O 0 C and filter it and dry it reduced pressure at 5O 0 C.

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Abstract

The present invention relates to process for preparation of tetrazoles of formula (I) from aromatic cyano derivatives of formula (II) comprising of treating the cyano compound of formula (II) with trialkyltin halide and metal azide in presence of base.

Description

PROCESS FOR PREPARATION OF TETRAZOLES FROM AROMATIC
CYANO DERIVATIVES
FIELD OF INVENTION
The present invention relates to process for preparation of tetrazoles of formula (I) from aromatic cyano derivatives of formula (II) comprising of treating the cyano compound of formula (II) with trialkyltin halide and metal azide in presence of base. This process is useful for preparation of various compounds belonging to the class of non-peptide angiotensin-II inhibitors such as Valsartan of formula (A), Candesartan of formula (B), Irbesartan of formula (C), Losartan of formula (D), Olmesartan of formula (E) and Tasosartan of formula (F).
Figure imgf000002_0001
Formula (I) Formula (II)
BACKGROUND OF THE INVENTION AND PRIOR ART
Valsartan of formula (A), Candesartan of formula (B), Irbesartan of formula (C), Losartan of formula (D), Olmesartan of formula (E) and Tasosartan of formula (F) are angiotensin II receptor antagonists also known as angiotensin receptor blockers (ARBs) and are useful for the treatment of hypertension and congestive heart failure. They act by inhibiting the action of angiotensin II on its receptors and prevent the increase in blood pressure produced by hormone-receptor interactions. These compounds contain a common structural feature - the 5-tetrazole group.
Figure imgf000002_0002
Figure imgf000003_0001
Valsartan of formula (A), Candesartan of formula (B), Irbesartan of formula (C), Losartan of formula (D), Olmesartan of formula (E) and Tasosartan of formula (F) are reported in US Patent No. 5,399,578, US Patent No. 5,196,444, US Patent No. 5,270,317, US Patent No. 5,138,069, US patent No. 5,616,599 and US Patent No. 5.149,699 respectively. The route commonly followed for obtaining the 5-tetrazole moiety in the desired compound is by carrying out cyclization of the corresponding cyano derivative in presence of organo- tin azides. These compounds are purified by column chromatography and if desired further recrystalization can be carried out. But these processes generally suffer by giving low yields, longer reaction times and final purification by tedious chromatographic techniques.
Hence there is a need to improvise the process for conversion of aromatic cyano derivatives to tetrazole compounds, thereby providing desired compound with high purity, better yields and shorter reaction times.
It was observed by the inventors of the present invention that use of base along with trialkyltin halide and metal azide results in improved yield, reduction in reaction time and high purity product. OBJECT OF THE INVENTION
The object of the present invention to provide a process of preparation of tetrazole of formula (I) from aromatic cyano derivatives of formula (II) which is high yielding, has shorter reaction times and gives desired compound with high purity.
Another object of the invention is to provide a process for preparing Valsartan, Candesartan, Irbesartan, Losartan, Olmesartan or Tesosartan, which is simple, easy to handle and cost effective.
SUMMARY OF THE INVENTION
According to the object of the invention, there is provided a process for preparing compound of formula (I) or a stereoisomer or salt thereof,
Figure imgf000004_0001
Formula (I) wherein R is selected from group comprising of formula (a), (b), (c), (d) or (e)
Figure imgf000004_0002
Formula (a) Formula (b) Formula (c) Formula (d) Formula (e)
wherein A, B and D are independently C, O, N or S and the dotted line represents a single or a double bond; R], R2, R3, Rt, Rs, R6, R7, Rs and R9 are independently selected from hydrogen, C1-6 alkyl, -CN, -NO2, -COOH, -COOCi-6 alkyl, -COORa (wherein Ra is benzyl, Ci-6 alkanoyloxy Ci-6 alkyl, C6-7 cycloalkanoyloxy C]-6 alkyl, Ci-6 alkoxycarbonyloxy Ci-6 alkyl, C5-6 cycloalkoxycarbonyloxy Ci-6 alkyl, (5-phenyl-2-oxo- l,3-dioxolen-4-yl)methyl group, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl group, (5- ethyl-2-oxo-l,3-dioxolen-4-yl)methyl group or a phthalidyl group), -CRbRcRd (Rb, Rc and Rd are independently -H, Ci-6 alkyl, Ci-6 alkanoyl, -OH or Ci-6 alkoxy ), -CONHR', - OR" (R' and R" are independently Ci-6 alkyl, aryl, aralkyl, alkoxyalkyl or amino alkyl), - OH, Ci-6 alkoxyCi-6 alkyl, Ci-6 alkylcarbonyl, halo, halo C]-6 alkyl, Ci-6 alkyl hydroxyl, Ci-6 alkylamino, C3-8 cycloalkyl attached directly to the ring, C3-8 heterocycloalkyl, Ci-6 alkoxy Ci-6 alkylamino, carboxy Ci-6 alkyl, Ci-6 alkyl-COO-Rx (Rx represents -H, Ci-C6 alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, 2-methyl- propyl or benzyl), pivaloyloxymethoxycarbonyl, 1-
(cyclohexyloxycarbonyloxy)ethoxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxy-carbonyl, isobutyryloxymethoxycarbonyl, l-(ethoxycarbonyloxy)ethoxycarbonyl, 1 -(acetyloxy)ethoxycarbonyl, 1 -(isobutyryloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyl oxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl; P is hydrogen or a tetrazole protecting group, comprising treating compound of formula (II)
Figure imgf000005_0001
Formula (II) wherein R is as defined above, with trialkyltin halide and metal azide in presence of base.
According to another aspect of the present invention, there is provided a process of preparing Valsartan or a stereoisomer or a precursor thereof, comprising reacting compounds of formula (Hd) with trialkyltin halide and metal azide in presence of base
Figure imgf000006_0001
Formula (Hd) wherein Rx represents hydrogen, Ci-C6 alkyl selected from methyl, ethyl, n-propyl, iso- propyl, n-butyl, tert-butyl, 2-methyl-propyl or benzyl to give Valsartan or a stereoisomer or a salt thereof.
Yet another embodiment of the present invention provides a process of preparing Candesartan or a stereoisomer or a ester or a precursor thereof comprising reacting compounds of formula (lib) with trialkyltin halide and metal azide in presence of base
Figure imgf000006_0002
wherein Ry represents -COOH and salts thereof, -COOMe, -COOEt, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, 1 -(cyclohexyloxycarbonyloxy)ethoxycarbonyl, 5-methyl- 2-oxo-l,3-dioxolen-4-ylmethyloxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxy-carbonyl, isobutyryloxymethoxycarbonyl, l-(ethoxycarbonyloxy)ethoxycarbonyl, l-(acetyloxy)ethoxycarbonyl, l-(isobutyryloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl or like to give Candesartan or a stereoisomer or a ester or a salt thereof.
According to yet another aspect of the present invention there is provided a process of preparing Irbesartan or a stereoisomer or a precursor thereof comprising reacting compounds of formula (Ha) with trialkyltin halide and metal azide in presence of base to give Irbesartan or a stereoisomer or a salt thereof.
Figure imgf000007_0001
According to yet another aspect of the present invention there is provided a process of preparing Losartan or a stereoisomer or a precursor thereof comprising reacting compounds of formula (lie) with trialkyltin halide and metal azide in presence of base to give Losartan or a stereoisomer or a salt thereof.
Figure imgf000007_0002
According to yet another aspect of the present invention there is provided a process of preparing Olmesartan or a stereoisomer or a precursor thereof comprising reacting compounds of formula (Hc') with trialkyltin halide and metal azide in presence of base to give Olmesartan or a stereoisomer or a salt thereof.
Figure imgf000008_0001
According to yet another aspect of the present invention there is provided a process of preparing Tasosartan or a stereoisomer or a precursor thereof comprising reacting compounds of formula (He) with trialkyltin halide and metal azide in presence of base to give Tasosartan or a stereoisomer or a salt thereof.
Figure imgf000008_0002
DETAILED DESCRIPTION OF THE INVENTION The inventors of the following invention have surprisingly found that preparation of tetrazoles of formula (I) from aromatic cyano derivatives of formula (II) takes place conveniently by using trialkyltin halide and metal azide in presence of base, giving high yield, shorter duration of reaction and increased purity.
The compound of formula (I) or a stereoisomer or salt thereof,
Figure imgf000009_0001
Formula (I) wherein R is selected from group comprising of formula (a), (b), (c), (d) or (e)
Figure imgf000009_0002
Formula (a) Formula (b) Formula (c) Formula (d) Formula (e)
wherein A, B and D are independently C, O, N or S and the dotted line represents a single or a double bond; R1, R2, R3, R4, R5, R6, R7, Rs and R9 are independently selected from hydrogen, Ci-6 alkyl, -CN, -NO2, -COOH, -COOCi-6 alkyl, -COORa (wherein Ra is benzyl, Ci-6 alkanoyloxy Ci-6 alkyl, C6-7 cycloalkanoyloxy Ci-6 alkyl, Ci-6 alkoxycarbonyloxy Ci-6 alkyl, C5-6 cycloalkoxycarbonyloxy Ci-6 alkyl, (5-phenyl-2-oxo- l,3-dioxolen-4-yl)methyl group, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl group, (5- ethyl-2-oxo-l,3-dioxolen-4-yl)methyl group or a phthalidyl group), -CRbRcRd (Rb, Rc and Rd are independently -H, Ci-6 alkyl, Ci-6 alkanoyl, -OH or Ci-6 alkoxy ), -CONHR', - OR" (R' and R" are independently Ci-6 alkyl, aryl, aralkyl, alkoxyalkyl or amino alkyl), - OH, Ci-6 alkoxyCi-6 alkyl, Ci-6 alkylcarbonyl, halo, halo Ci-6 alkyl, Ci-6 alkyl hydroxyl, Ci-6 alkylamino, C3-8 cycloalkyl attached directly to the ring, C3-8 heterocycloalkyl, Cj-6 alkoxy Ci-6 alkylamino, carboxy Ci-6 alkyl, Cj-6 alkyl-COO-Rx (Rx represents -H, Ci-C6 alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, 2-methyl- propyl or benzyl), pivaloyloxymethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy)ethoxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxy-carbonyl, isobutyryloxymethoxycarbonyl, l -(ethoxycarbonyloxy)ethoxycarbonyl, l-(acetyloxy)ethoxycarbonyl, 1 -(isobutyryloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl; P is hydrogen or a tetrazole protecting group, comprising treating compound of formula (II)
Figure imgf000010_0001
Formula (II) wherein R is as defined above, with trialkyltin halide and sodium azide in presence of base.
The reaction can be carried out in presence of suitable solvent selected from the group comprising of aliphatic, cycloaliphatic and aromatic hydrocarbon, such as an C5-C10 alkane e. g. heptane, a cycloalkane such as cyclohexane ; an alkylated C3-C7 cycloalkane such as methyl-cyclohexane or 1, 3-dimethyl-cyclohexane, an alkylated benzene such as ethylbenzene, toluene, xylene, cumene, or mesitylene ; a halogenated aromatic solvent such as chlorobenzene, o-, m- or p-chlorotoluene, dichlorobenzene, and trifluoromethylbenzene which may be further substituted e.g. by C1-C7 alkyl or C1-C7 alkoxy; an halogenated hydrocarbon like such as methylenedichloride, ethylenedichloride or chloroform; a halogenated aromatic compound, such as chlorobenzene; an ether, such as tetrahydrofuran, diisoproyl ether; an ketone, such as diisobutyl ketone, methyl isobutyl ketone; high boiling aprotic solvents such as dioxane, dimethylformamide, dimethylacetamide, dimethylsulphoxide; or mixtures thereof.
The reaction is carried out at temperature ranging from about 00C to about reflux temperature of the solvent, more preferably at about 2O0C to about 2500C. The reaction time varies from about 1 hour to about 150 hours, more preferably from about 10 hours to about 50 hours.
The trialkyltin halide can be trialkyltin chloride selected from group of trimethyltin chloride, triethyltinchloride, tributyltinchloride and like. The metal azide can be selected from inorganic azide like sodium, potassium or lithium azide. The base is a nitrogeneous base selected form group of primary, secondary or tertiary amines for e.g. isopropyl amine, diethyl amine, triethyl amine, tributyl amine, diisopropyl ethyl amine and like.
After the completion of the reaction the compound can be isolated by conventional methods or by methods known to person skilled in art.
It is also possible to prepare 5-tetrazole protected compound protected with suitable protecting group selected from trityl, monomethyoxytrityl, dimethoxytrityl, benzhydryl, acyl, benzyl which is unsubstituted or substituted, for example by nitro, such as 4- nitrobenzyl, lower alkoxymethyl, such as methoxy- and ethoxymethyl, lower alkylthiomethyl, such as methylthiomethyl, silyl, such as tri-lower alkylsilyl, for example dimethyl-tert-butyl- and triisopropylsilyl, and 2-cyanoethyl, also lower alkoxy-lower alkoxymethyl, such as 2-methoxyethoxymethyl, benzyloxymethyl, phenacyl or like by process known to person skilled in general art.
It is also possible to carry out reaction in presence of organo-tin azides or any cyclizing agent known in art for conversion of cyano group to tetrazole group.
According to the present invention process for the preparation of Valsartan of formula (A) or a stereoisomer or a precursor thereof, comprises treating compound of formula (II)
Figure imgf000011_0001
Formula (II) wherein R is selected from compound of formula (d)
*VR7
Formula (d) wherein A is N; R6 is valeroyl and R7 is L-valine or its ester derivative, with trialkyltin halide and metal azide in presence of base, to give Valsartan or a stereoisomer or a salt thereof. Thus compound of formula (II) can be represented by compound of formula (Hd)
Figure imgf000012_0001
Formula (Hd) wherein Rx represents -H, C]-C6 alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, 2-methyl-propyl or benzyl.
The reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
Moreover, in accordance with the present invention, there is given process of preparing Candesartan of formula (B) or a stereoisomer or a ester or a precursor thereof, comprising treating compound of formula (II)
Figure imgf000012_0002
Formula (II) wherein R is selected from compound of formula (b)
Figure imgf000012_0003
Formula (b) wherein A and B are N; C is O; the dotted line represents a double bond; R3 is a carboxyl group or its ester and Ri is ethyl, with trialkyltin halide and metal azide in presence of base, to give Candesartan or a stereoisomer or a salt or a ester thereof. Thus compound of formula (II) can be represented by compound of formula (lib)
Figure imgf000013_0001
wherein Ry represents -COOH and salts thereof, -COOMe, -COOEt, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, l-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, 5-methyl- 2-oxo-l,3-dioxolen-4-ylmethyloxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxy-carbonyl, isobutyryloxymethoxycarbonyl, l-(ethoxycarbonyloxy)ethoxycarbonyl, 1 -(acetyloxy)ethoxycarbonyl, 1 -(isobutyryloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl or like.
The reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
According to present invention, there is further provided a process for preparation of Irbesartan of formula (C) or a stereoisomer or a precursor thereof, comprising treating compound of formula (II)
Figure imgf000013_0002
Formula (II) wherein R is selected from compound of formula (a)
Figure imgf000014_0001
Formula (a) wherein A and B are N; the dotted line represents a double bond; R] is n-butyl and R2 is a cyclopentyl ring directly attached to the imidazole ring, forming a spiro compound, with trialkyltin halide and metal azide in presence of base, to give Irbesartan or a stereoisomer or a salt thereof. Thus compound of formula (II) can be represented by compound of formula (Ha)
Figure imgf000014_0002
The reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
According to present invention, there is given a process of preparing Losartan of formula (D) or a stereoisomer or a precursor thereof, comprising treating compound of formula
(H)
Figure imgf000014_0003
Formula (II) wherein R is selected from compound of formula (c)
Figure imgf000015_0001
Formula (c) wherein A and B are N; R1 is n-butyl and R5 is hydroxymethyl and R4 is chloro, with trialkyltin halide and metal azide in presence of base, to give Losartan or a stereoisomer or a salt thereof. Thus compound of formula (II) can be represented by compound of formula (lie)
Figure imgf000015_0002
The reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
According to present invention, there is given a process of preparing Olmesartan of formula (E) or a stereoisomer or a precursor thereof, comprising treating compound of formula (II)
Figure imgf000015_0003
Formula (II) wherein R is selected from compound of formula (c)
Figure imgf000016_0001
Formula (c) wherein A and B are N; Ri is n-propyl and R5 is (5-methyl-2-oxo-l,3-dioxol-4- yl)carboxylate and R4 is 1 -hydroxy- 1-methylethyl, with trialkyltin halide and metal azide in presence of base, to give Olmesartan or a stereoisomer or a salt thereof. Thus compound of formula (II) can be represented by compound of formula (Hc')
Figure imgf000016_0002
The reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
According to present invention, there is given a process of preparing Tasosartan of formula (F) or a stereoisomer or a precursor thereof, comprising treating compound of formula (II)
Figure imgf000016_0003
Formula (II) wherein R is selected from compound of formula (e)
Figure imgf000017_0001
Formula (e) wherein A, B and D are N; Rg and R9 is methyl, with trialkyltin halide and metal azide in presence of base, to give Tasosartan or a stereoisomer or a salt thereof. Thus compound of formula (II) can be represented by compound of formula (He)
Figure imgf000017_0002
The reaction conditions and the reagents used for this reaction are such as herein described above in the preparation of compound of formula (I).
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.
Example 1
Preparation of Irbesartan In a 3 necked 250 ml 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 (5.0 g), o-xylene (25.0 ml) and tri n.butyltin chloride (12.7g), sodium azide (2.5g) and diisopropylethyl amine (0.5g) and stir it. The reaction mixture was heated to reflux under stirring for 12 hours. The reaction mixture was cooled to ambient temperature and 2N sodium hydroxide (50ml) was added and stirred for 30 minutes. The mixture was filtered through hyflo bed and the phases were separated and aqueous phase was washed with o- xylene and isopropyl ether. The aqueous phase was treated with activated charcoal and filtered through hyflo bed. The filtrate was cooled 5-1O0C and pH was adjusted to 4-5 by 3N hydrochloric acid on pH meter. The product was filtered, washed, dried under vacuum at 6O0C and crystallized in rectified spirit.
Example 2
Preparation of Valsartan
Step (a): Preparation of N-[(2'-cyanobiphenyl-4yI)methyl]-N-pentanoyl-(L)-vaIine methyl ester
A solution of N-[(2'-cyanobiphenyl-4yl)methyl]-(L)-valine methyl ester oxalate salt (25g) in xylene (125ml) and water (100 ml), was treated with potassium carbonate (29.8g) and valeroyl chloride (11.2g) at 0-50C for 2 hours. The layers were separated and the organic layer was washed with bicarbonate solution and brine successively. The organic layer was then concentrated to obtain the title compound as yellow coloured liquid or it can be used as such for the next step.
Step (b): Preparation of S)-N-(l-Carboxy-2-methyI-prop-l-yI)-N-pentanoyl-N-[2'- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl]-amine (Valsartan) To a solution of N-[(2'-cyanobiphenyl-4yl)methyl]-N-pentanoyl-(L)-valine methyl ester obtained in step (a), tri n.butyltin chloride (60.1 g), sodium azide (11.85g) and triethylamine (2.5g) was refluxed for 8-12 hours. It was cooled and stirred with 10% sodium hydroxide solution for 20-24 hours to complete hydrolysis of Valsartan methyl ester. The aqueous layer was separated, washed with dichloromethane, acidified with acetic acid and extracted with dichloromethane. The dichloromethane layer was washed with water, concentrated and the material was isolated using cyclohexane.
Example 3
Preparation of Candesartan acid
In a 3 necked 250 ml round bottom flask equipped with mechanical stirrer, was charged with methyl l-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7-carboxylate
(5.0 g), o-xylene (25.0 ml) and tri n.butyltin chloride (11.7g, sodium azide (2.3g) and diisopropylethyl amine (0.5g) and stir it. The reaction mixture was heated to reflux under stirring for 12 hours. The reaction mixture was cooled to ambient temperature and 2N sodium hydroxide (50ml) was added and the reaction mixture was heated to reflux under stirring for 12 hours. The reaction mixture was cooled to ambient temperature. The mixture was filtered through hyflo bed and the phases were separated and aqueous phase was washed with o-xylene and isopropyl ether. The aqueous phase was treated with activated charcoal and filtered through hyflo bed. The filtrate was cooled 5-1O0C and pH was adjusted to 4-5 by 3N hydrochloric acid on pH meter. The product was filtered, washed, dried under vacuum at 6O0C to give product i.e. 2-ethoxy- l-[(2'-{lH-tetrazole- 5-yl}biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid.
Example 4
Preparation of Candesartan cilexetil
In a 3 necked 250 ml round bottom flask equipped with mechanical stirrer, was charged with (±) 2-ethoxy-l-[(2'-cyanobiphenyl-4-yl)-methyl]-lH-benzimidazole-7-carboxylic acid, l {[(Cyclohexyl-oxy)carbonyl]oxyl} ethyl ester (5.67g), o-xylene (25.0 ml) and tri n.butyltin chloride (9.76g), sodium azide (1.95g) and diisopropylethyl amine (0.56g) and stir it. The reaction mixture was heated to reflux under stirring for 12 hours. The reaction mixture was distilled at reduced pressure and remaining product dissolved by alcohol (20 ml). Then (6M, 10 ml) HCl is added and extract with ethyl acetate (2 X 30 ml) and combine organic layer and wash it with water. Distilled out organic layer and residue dissolve in alcohol (15 ml) and water (5 ml) and stir for 7 hour at 2O0C to 3O0C and filter it and dry it reduced pressure at 5O0C.
Recrystallised by alcohol/water (4/1) to give product i.e. (±)-l- (cyclohexyloxycarbonyloxy) ethyl-2-ethoxy- l -[(2'-{lH- tetrazole-5-yl} biphenyl-4-yl)- methyl] benzimidazole-7-carboxylate.
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 preparation of compound of formula (I) or a stereoisomer or salt thereof,
Figure imgf000020_0001
Formula (I) wherein R is selected from group comprising of formula (a), (b), (c), (d) or (e)
Figure imgf000020_0002
Formula (a) Formula (b) Formula (c) Formula (d) Formula (e) wherein A, B and D are independently C, O, N or S and the dotted line represents a single or a double bond; R1, R2, R3, R4, R5, R6, R7, R8 and R9 are independently selected from hydrogen, C1-6 alkyl, -CN, -NO2, -COOH, -COOC1-6 alkyl, -COORa (wherein Ra is benzyl, Ci-6 alkanoyloxy Ci-6 alkyl, C6-7 cycloalkanoyloxy Ci-6 alkyl, Ci-6 alkoxycarbonyloxy Ci-6 alkyl, Cs-6 cycloalkoxycarbonyloxy Ci-6 alkyl, (5-phenyl-2-oxo-l,3-dioxolen-4-yl)methyl group, (5-methyl-2-oxo-l,3-dioxolen-
4-yl)methyl group, (5-ethyl-2-oxo-l,3-dioxolen-4-yl)methyl group or a phthalidyl group), -CRbRcRd (Rb, Rc and Rd are independently -H, Cj-6 alkyl, Ci-6 alkanoyl, -OH, Ci-6 alkoxy or Ci-6 alkoxycarbonyl), -CONHR', -OR" (R' and R" are independently Ci-6 alkyl, aryl, aralkyl, alkoxyalkyl or amino alkyl), -OH, Ci-6 alkoxyCi-6 alkyl, Ci-6 alkylcarbonyl, halo, halo Ci-6 alkyl, Ci-6 alkyl hydroxyl, Ci-6 alkylamino, C3-S cycloalkyl attached directly to the ring, C3-8 heterocycloalkyl, Ci- β alkoxy Ci-6 alkylamino, carboxy Ci-6 alkyl, Ci-6 alkyl-COO-Rx (Rx represents - H, Ci-C6 alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert- butyl, 2-methyl-propyl or benzyl), pivaloyloxymethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy)ethoxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxy-carbonyl, isobutyryloxymethoxycarbonyl, l-(ethoxycarbonyloxy)ethoxycarbonyl, l-(acetyloxy)ethoxycarbonyl, 1 -(isobutyryloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl; P is hydrogen or a tetrazole protecting group, comprising treating compound of formula (II)
Figure imgf000021_0001
Formula (II) wherein R is as defined above, with trialkyltin halide and metal azide in presence of base.
2. A process according to claim 1, wherein base is a nitrogeneous base.
3. A process according to claim 2, wherein nitrogeneous base is selected from the group comprising primary, secondary or tertiary amines for e.g. isopropyl amine, diethyl amine, triethyl amine, tributyl amine, diisopropyl ethyl amine or mixture thereof.
4. A process according to claim 1, wherein solvent is selected from the group comprising aliphatic, cycloaliphatic and aromatic hydrocarbon, such as an C5-C1O alkane e. g. heptane, a cycloalkane such as cyclohexane ; an alkylated C3-C7 cycloalkane such as methyl-cyclohexane or 1, 3-dimethyl-cyclohexane, an alkylated benzene such as ethylbenzene, toluene, xylene, cumene, or mesitylene; a halogenated aromatic solvent such as chlorobenzene, o-, m- or p-chlorotoluene, dichlorobenzene, and trifluoromethylbenzene which may be further substituted e.g. by C1-C7 alkyl or Ci-C7 alkoxy; an halogenated hydrocarbon like such as methylenedichloride, ethylenedichloride or chloroform; a halogenated aromatic compound, such as chlorobenzene; an ether, such as tetrahydrofuran, diisoproyl ether; an ketone, such as diisobutyl ketone, methyl isobutyl ketone; high boiling aprotic solvents such as dioxane, dimethylformamide, dimethylacetamide, dimethylsulphoxide; or mixtures thereof.
5. A process according to claim 1, wherein trialkyltin halide is a trialkyltin chloride.
6. A process according to claim 5, wherein trialkyltin chloride selected from group comprising trimethyltin chloride, triethyltinchloride, tributyltinchloride or mixture thereof.
7. A process according to claim 1, wherein metal azide is inorganic azide.
8. A process according to claim 7, wherein inorganic azide is selected from group comprising sodium azide, potassium azide or lithium azide.
PCT/IN2006/000346 2005-09-23 2006-09-08 Process for preparation of tetrazoles from aromatic cyano derivatives Ceased WO2007054965A2 (en)

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WO2009125416A2 (en) 2008-04-07 2009-10-15 Hetero Research Foundation Process for preparation of valsartan intermediate
WO2009001375A3 (en) * 2007-06-27 2011-01-20 Matrix Laboratories Ltd Improved process for preparing pure valsartan
US8236843B2 (en) 2008-09-02 2012-08-07 Elder Pharmaceuticals Ltd. Anti inflammatory compounds
US8623928B2 (en) 2009-11-12 2014-01-07 National Research Council Of Canada Polymers of intrinsic microporosity containing tetrazole groups
US9062003B2 (en) 2010-10-06 2015-06-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
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Publication number Priority date Publication date Assignee Title
WO2003089417A1 (en) * 2002-04-15 2003-10-30 Dr. Reddy's Laboratories Limited Novel crystalline forms of (s)-n-(1-carboxy-2-methyl-prop-1-yl) -n-pentanoyl-n- [2’-(1h-tetrazol-5-yl-)- biphenyl-4-yl methyl] amine (valsartan)
WO2005051929A1 (en) * 2003-11-28 2005-06-09 Ranbaxy Laboratories Limited Conversion of aromatic nitriles into tetrazoles

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WO2009001375A3 (en) * 2007-06-27 2011-01-20 Matrix Laboratories Ltd Improved process for preparing pure valsartan
US8258312B2 (en) 2007-06-27 2012-09-04 Mylan Laboratories Ltd Process for preparing pure valsartan
WO2009125416A2 (en) 2008-04-07 2009-10-15 Hetero Research Foundation Process for preparation of valsartan intermediate
US8492577B2 (en) 2008-04-07 2013-07-23 Hetero Research Foundation Process for preparation of valsartan intermediate
US8236843B2 (en) 2008-09-02 2012-08-07 Elder Pharmaceuticals Ltd. Anti inflammatory compounds
US8623928B2 (en) 2009-11-12 2014-01-07 National Research Council Of Canada Polymers of intrinsic microporosity containing tetrazole groups
US9062003B2 (en) 2010-10-06 2015-06-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9872860B2 (en) 2010-10-06 2018-01-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10314845B2 (en) 2010-10-06 2019-06-11 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10660898B2 (en) 2010-10-06 2020-05-26 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US11655220B2 (en) 2020-10-22 2023-05-23 Hetero Labs Limited Process for the preparation of angiotensin II receptor blockers

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