WO2006097121A1 - Procede de preparation de composes biphenyltetrazole - Google Patents

Procede de preparation de composes biphenyltetrazole Download PDF

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Publication number
WO2006097121A1
WO2006097121A1 PCT/EP2005/002774 EP2005002774W WO2006097121A1 WO 2006097121 A1 WO2006097121 A1 WO 2006097121A1 EP 2005002774 W EP2005002774 W EP 2005002774W WO 2006097121 A1 WO2006097121 A1 WO 2006097121A1
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Prior art keywords
formula
compound
substituted
group
optionally
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Ceased
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PCT/EP2005/002774
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English (en)
Inventor
Serafettin ÜNSAL
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ULKAR KIMYA SANAYII VE TICARET AS
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ULKAR KIMYA SANAYII VE TICARET AS
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Priority to PCT/EP2005/002774 priority Critical patent/WO2006097121A1/fr
Priority to PCT/TR2006/000007 priority patent/WO2006098705A1/fr
Priority to EP06717222A priority patent/EP2001869A1/fr
Publication of WO2006097121A1 publication Critical patent/WO2006097121A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a method for producing biphenyl- tetrazole compounds of the general formula
  • R 1 being a straight chain or branched C j :-C 6 -alkyl group
  • R 2 and R 3 being the same or different and being selected from straight-chain or branched, saturated or unsaturated C 1 -C 20 - ⁇ IkYl groups, which can optionally be substituted with halogen atoms; straight-chain or branched, saturated or unsaturated c i- C 20 -heteroalkyl groups, which can optionally be substituted with halogen atoms; aromatic or aliphatic C 3 -C 18 -hydrocarbon rings, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; aromatic or aliphatic C 3 -C 18 -heterocycles, which can optionally be substituted with one or more selected from the group consisting of alkyl, alkenyl, al
  • R is the same as in formula (I), with a deprotecting agent in a solvent.
  • biphenyl-tetrazole compounds of formula (I) form among others the backbone of a number of known antihypertensive agents, in which R is for example
  • Antihypertensive agents comprising such a biphenyl-tetrazole backbone belong to a group of angiotensin II-receptor antagonists which are generally referred to as "sartans".
  • Sartans which show such a biphenyl-tetrazole backbone include Cande- sartan (R is IV), Irbesartan (R is V), Losartan (R is VI), Olmesartan (R is VII) and Valsartan (R is VIII). These agents work by blocking the action of angiotensin II on its receptor. Angiotensin II mediates among others smooth muscle contraction especially in blood vessels. Angiotensin II- receptor antagonists therefore act as powerful vasodilators.
  • the compounds of formula (II) include precursors to the above sartans which are protected by a triphenylmethyl-protecting group.
  • This group is commonly also referred to as a trityl- protecting group and has the following formula
  • the compounds of formula (II) are formed as intermediates in the synthesis of the corresponding sartans of formula (I). In a further step, they need to be deprotected in order to form the desired active compounds.
  • EP 0 733 366 Bl describes the removal of the trityl-protecting group by treating the trityl-protected precursor of Losartan with hydrochloric acid (Example 316). It is further known from WO 03/093262 A2 with respect to Losar- tan that the trityi-protecting group can be removed using an acid in a diluent comprising a liquid ketone.
  • R 4 , R 5 are the same or different and hydrogen or straight-chain or branched groups and wherein A is an organic or inorganic monovalent anion.
  • the reaction of this method therefore proceeds with high yields and results in an easily purified product.
  • the compounds of formula (III) employed are less corrosive and much easier to handle than e.g. strong mineral acids due to their more moderate pH-value .
  • R 2 and R 3 either together form an imidazole ring, which can be substituted or unsubstituted, part of a fused ring system and partially or fully hydrogenated, or R 2 and R 3 are alkyl residues comprising at least one carboxy group.
  • R 1 is preferably -CH 2 -.
  • the compound of formula (I) is a compound that shows angiotensin II-receptor antagonistic activity.
  • it is selected from the group consisting of Candesartan, Irbesartan, Losartan, Olmesartan, and VaI- sartan, whereby Irbesartan and Losartan are particularly preferred.
  • Such compounds are powerful vasodilators and antihypertensive agents and therefore are of high commercial interest.
  • R 4 and R 5 are both hydrogen .
  • A is preferably a monovalent anion of a mineral acid. More preferably the compound of formula (III) is selected from the group consisting of hydroxylammonium sulfates and hydroxylammo- nium chlorides.
  • the solvent is a protic solvent, preferably an alcohol, more preferably a and especially an alcohol selected from the group consisting of methanol, ethanol and isopropanol.
  • protic solvents particularly alcohols
  • Methanol, ethanol and isopropanol have thereby been shown to be the most suitable solvents .
  • alcohols as solvents further has the advantage that trityl-methanol which is formed during the deprotection reaction readily precipitates from such solvents, further facilitating the purification of the desired product.
  • the method further comprises isolating formed trityl-methanol from the solvent, preferably by precipitation.
  • the trityl-protecting group is removed from the biphenyl- tetrazole compounds of formula (II) in form of trityl-methanol.
  • the trityl-methanol is formed by the reaction of the trityl- cation formed during the deprotection with residual water present in the solvent. The isolation of the formed trityl- methanol from the solvent thereby serves two purposes.
  • trityl-methanol helps the purification of the desired de- protected compound of formula (I) and second it provides a source of trityl-methanol .
  • the so obtained trityl-methanol can be used again e.g. in the synthesis of the trityl-protected compounds of formula (II), saving resources and thus making the process more economical as well as more environmentally friendly.
  • Precipitation is a particularly preferred method for isolating the formed trityl-methanol since it can be effected by simply cooling the reaction mixture without the need for more complex purification techniques such as extractions or column chromatography.
  • the compound of formula (II) is reacted with the compound of formula (III) at a temperature from 50 to 70 0 C, preferably from 55 to 65 0 C.
  • the compound of formula (II) is reacted with the compound of formula (III) for 1.5 to 4.5 hours, preferably for 2.0 to 3.5 hours.
  • a trityl-protected biphenyl-tetrazole compound of formula (II) is heated together with a compound of formula (III) in a solvent at 50 to 70 0 C while stirring.
  • the progression of the reaction is monitored by HPLC.
  • the stirring is stopped and the solution is further aged at the same temperature .
  • the pH of the solution is raised by the addition of base to a value of 3.5 to 5.0.
  • the solution is cooled to 0 to 5 0 C and stirred, while trityl-methanol precipitates from the solution.
  • the resulting suspension is filtered and the precipitated trityl-methanol is washed with more cold solvent and can be used again in the synthesis of trityl- protected compounds .
  • the solvent and free hydroxylammonium compounds are removed from the filtrate under reduced pressure in order to obtain the crude compound of formula ( I ) .
  • the so obtained crude product can then be further processed, for example by recristallization.
  • the resulting slurry was filtered and the filter cake containing precipitated trityl-methanol was washed with 50 ml cold methanol and sucked to dryness. 210 g wet trityl-methanol were recovered.
  • the pH of the mixture was measured as 2.4 and 4.5 ml of triethylamine were added to bring the pH to 3.5. Meanwhile, colorless crystals of trityl-methanol started to precipitate. The obtained suspension was cooled to 0 to 5 0 C and stirred at this temperature for 2 more hours .
  • the obtained suspension was filtered and the precipitated trityl-methanol was washed with 20 ml cold isopropanol. 21.6 g of wet trityl-methanol were recovered.
  • the isopropanol was removed from the filtrate under reduced pressure. 95 ml ethyl acetate were added to the obtained residue and the resulting suspension was stirred for 1 hour at 5 to 10 0 C. The obtained homogeneous precipitate in ethyl acetate was filtered and washed with 10 ml cold ethyl acetate. 49.2 g of colorless crystals of wet Losartan were obtained which were dried at 60 0 C under vacuum to yield 36 g of a powder (93.8 % yield).
  • a reaction vessel equipped with a reflux condenser was charged with 3 1 methanol and 138 g hydroxylammonium chloride. The mixture was stirred at room temperature for half an hour and then heated at 40 °C for a further half hour. To this solution, 600 g trityl-protected Irbesartan were added in portions. After all trityl-protected Irbesartan had been added, the reaction mixture was heated to 60 to 65 0 C and stirred for 2 hours at this temperature. The obtained slightly yellow solution was analyzed by HPLC and it was found that 99.4 % of the trityl- protected Irbesartan had been consumed. The mixture was cooled to 40 0 C.
  • the pH of the solution was measured as 3.1 and 42 ml of triethylamine were added to bring the pH to 4.55.
  • the reaction mixture was cooled to 0 0 C and stirred for 1 hour to precipitate the formed trityl methanol resulting in a slurry.
  • the slurry was filtered and the obtained filter cake was sucked to dryness and washed with 100 ml cold methanol.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le procédé de l’invention, visant à produire des composés biphényltétrazole en déprotégeant des composés de formule (II), propose d’utiliser des sels hydroxylammonium pour éliminer le groupe protecteur Ph3C-.
PCT/EP2005/002774 2005-03-16 2005-03-16 Procede de preparation de composes biphenyltetrazole Ceased WO2006097121A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/EP2005/002774 WO2006097121A1 (fr) 2005-03-16 2005-03-16 Procede de preparation de composes biphenyltetrazole
PCT/TR2006/000007 WO2006098705A1 (fr) 2005-03-16 2006-03-15 Procede de fabrication de composes du biphenyl-tetrazole
EP06717222A EP2001869A1 (fr) 2005-03-16 2006-03-15 Procede de fabrication de composes du biphenyl-tetrazole

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2005/002774 WO2006097121A1 (fr) 2005-03-16 2005-03-16 Procede de preparation de composes biphenyltetrazole

Publications (1)

Publication Number Publication Date
WO2006097121A1 true WO2006097121A1 (fr) 2006-09-21

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Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2005/002774 Ceased WO2006097121A1 (fr) 2005-03-16 2005-03-16 Procede de preparation de composes biphenyltetrazole
PCT/TR2006/000007 Ceased WO2006098705A1 (fr) 2005-03-16 2006-03-15 Procede de fabrication de composes du biphenyl-tetrazole

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/TR2006/000007 Ceased WO2006098705A1 (fr) 2005-03-16 2006-03-15 Procede de fabrication de composes du biphenyl-tetrazole

Country Status (1)

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WO (2) WO2006097121A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2365966A4 (fr) * 2008-12-12 2012-05-09 Pharmacostech Co Ltd Procédé d'élimination du groupe protecteur triphénylméthane

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0733366A2 (fr) * 1988-01-07 1996-09-25 E.I. Du Pont De Nemours And Company Compositions pharmaceutiques comprenant des imidazoles comme antagonistes d'angiotensine II et des diurétiques
WO2003013369A1 (fr) * 2001-08-03 2003-02-20 Aesculap Ag & Co. Kg Instrument chirurgical permettant de placer une bande d'incontinence urinaire dans le bas-ventre de patients
US20040224998A1 (en) * 2003-05-06 2004-11-11 Ashok Kumar Losartan potassium synthesis

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7041832B2 (en) * 2002-04-29 2006-05-09 Tava Pharmaceutical Industries, Ltd. Processes for preparing losartan and losartan potassium
ES2273041T3 (es) * 2002-07-16 2007-05-01 Teva Pharmaceutical Industries Ltd. Nueva sintesis de irbesartan.
US20050250827A1 (en) * 2004-05-05 2005-11-10 Etinger Marina Y Preparation of candesartan cilexetil in high purity
WO2006050922A1 (fr) * 2004-11-11 2006-05-18 Lek Pharmaceuticals D.D. Procede pour la synthese de tetrazoles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0733366A2 (fr) * 1988-01-07 1996-09-25 E.I. Du Pont De Nemours And Company Compositions pharmaceutiques comprenant des imidazoles comme antagonistes d'angiotensine II et des diurétiques
WO2003013369A1 (fr) * 2001-08-03 2003-02-20 Aesculap Ag & Co. Kg Instrument chirurgical permettant de placer une bande d'incontinence urinaire dans le bas-ventre de patients
US20040224998A1 (en) * 2003-05-06 2004-11-11 Ashok Kumar Losartan potassium synthesis

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2365966A4 (fr) * 2008-12-12 2012-05-09 Pharmacostech Co Ltd Procédé d'élimination du groupe protecteur triphénylméthane

Also Published As

Publication number Publication date
WO2006098705A1 (fr) 2006-09-21

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