WO2006098705A1 - Procede de fabrication de composes du biphenyl-tetrazole - Google Patents

Procede de fabrication de composes du biphenyl-tetrazole Download PDF

Info

Publication number
WO2006098705A1
WO2006098705A1 PCT/TR2006/000007 TR2006000007W WO2006098705A1 WO 2006098705 A1 WO2006098705 A1 WO 2006098705A1 TR 2006000007 W TR2006000007 W TR 2006000007W WO 2006098705 A1 WO2006098705 A1 WO 2006098705A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
substituted
group
optionally
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/TR2006/000007
Other languages
English (en)
Inventor
Tuncer Aslan
Tuba Bicer
Yildiz Gulkok
Selda Turhan
Melek Koroglu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ULKAR KIMYA SANAYII VE TICARET AS
Original Assignee
ULKAR KIMYA SANAYII VE TICARET AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ULKAR KIMYA SANAYII VE TICARET AS filed Critical ULKAR KIMYA SANAYII VE TICARET AS
Priority to EP06717222A priority Critical patent/EP2001869A1/fr
Publication of WO2006098705A1 publication Critical patent/WO2006098705A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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 Q-C ⁇ -alkyl group; and R 2 and R 3 being the same or different and being selected from
  • -aromatic or aliphatic Cs-Qs-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, alkynyl, carboxy, hydroxy, amine, nitro, thiol, sulfoxy, sulfone groups, which can optionally be substituted and/or form further rings, and halogen atoms; whereby R 2 and R 3 together can form an aromatic or aliphatic C 3 -C 18 -heterocycle, which can optionally be substituted with one
  • R is the same as in Formula (I) with a deprotecting agent in a mixture of solvents in the presence of small amount of water.
  • 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 Candesartan ( R is III), Irbesartan (R is IV) 3 Losartan (R is V), Olmesartan (R is VI) and Valsartan (R is VII).
  • 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).
  • the main problem with this patent is that the given process is very complicated due to the insolubility of the Tritiyl Losartan in methanol in the presence of the aqueous acid and the other sartans will show similar behavior.
  • methoxytriphenylmethane is formed instead of triphenylmethanol.
  • the isolation of methoxytriphenylmethane is much easier than former compound due to the polarity difference.
  • Another object is that formation of methoxytriphenylmethane is not acid depended and always forms in the methanol containing mixtures.
  • a third object of this invention is to treat the compound of the formula (I) with ethyl acetate at a temperature that is below 40 0 C to prevent the reaction of the compound (I) with ethyl acetate and to minimize the formation of acetyl sartan.
  • sartans are treated with ethyl acetate according to the process of this invention; the amount of acetyl sartan impurity is below 0.1%.
  • Treating process of this invention is carried out at a temperature that is below 40 0 C 5 preferably at 20 to 30 0 C due to the reaction of the tetrazole ring of the sartans with ethyl acetate to form acetyl sartans as shown in general formula.
  • Wherin R is the same as in Formula I.
  • Acetyl saltans is appear as an impurity in the final product and difficult to separate from the final compound by using common purification method like crystallization or extraction.
  • Any compound act as a source of H + -ions to remove the trityl -protecting group can be used for the deprotection reaction such as mineral acid like hydrochloric acid, sulfuric acid or hydroxylammonium salts, like hydroxylamine hydrochloride or sulfate. Only one or two equivalent of mineral acid or ammonium salts is used during the deprotection reaction. Because of the low water content of the reaction mixture the reaction proceeds at a more moderate pH value than the agents used in previous examples and results in high yields with easily purified product.
  • 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 or alkoxy 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 Valsartan, whereby Irbesartan and Losartan are particularly preferred.
  • the reaction is carried in a mixture of solvents in the presence of small amount of water
  • the solvents are protic solvents, preferably an alcohol- ketone mixture and/or alcohol-alcohol-ketone mixture, more preferably C 1 -C 6 alcohols and C 3 -C 6 ketone mixture and especially alcohol selected from the group consisting of methanol, ethanol and isopropanol and especially a ketone selected from the group consisting of acetone, methylisobutylketone and tert-butylmethylketone.
  • protic solvent mixtures particularly alcohols and ketones, especially mixture of C 1 -C 6 alcohols and C 3 -C 6 ketones give the best results with regard to yield as well as solubility of all agents involved. Mixtures of methanol/acetone and methanol/isoprapanol/acetone have thereby been shown to be the most suitable solvents.
  • alcohol-ketone and/or alcohol-alcohol-ketone mixtures as solvent further has the advantage that methoxytriphenylmethane (the compound is characterized by 1 H-NMR, 13 C-NMR, DEPT and MS) which is formed during the deprotection reaction readily precipitates from such solvent mixtures, further facilitating the purification of the desired product.
  • methoxytriphenylmethane the compound is characterized by 1 H-NMR, 13 C-NMR, DEPT and MS
  • the method further comprises isolating formed methoxytriphenylmethane from the solvent preferably by precipitation.
  • the trityl-proteeting group is removed from the biphenyltetrazole compound of the formula (II) in form of methoxytriphenylmethane.
  • the methoxytriphenylmethane is formed by the reaction of the trityl cation formed during the deprotection with methanol present. The isolation of the formed methoxytriphenylmethane from the solvent thereby serves two purposes.
  • methoxytriphenylmethane helps the purification of the desired deprotected compound of the formula (I) and second it provides a source of methoxytriphenylmethane.
  • the so obtained methoxytriphenylmethane can be easily converted to the tritylchloride and used again in the synthesis of the trityl protected compounds of the 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 methoxytriphenylmethane since it can be affected by simply stirring the mixture at room temperature without the need for more complex purification technique such as column chromatography.
  • an acid is reacted with the compound of formula (II) at a temperature from 20 to 40 0 C, preferably from 20 to 25 0 C
  • the solvent is a mixture of protic solvents, particularly, alcohols and ketones, preferably a C 1 -C 6 alcohol and a C 3 -C 6 ketone, and especially an alcohol selected from the group consisting of methanol, ethanol and isopropanol, a ketone selected from the group consisting of acetone, methylisobutylketone, and tert- butylmethylketone.
  • protic solvents particularly, alcohols and ketones, preferably a C 1 -C 6 alcohol and a C 3 -C 6 ketone, and especially an alcohol selected from the group consisting of methanol, ethanol and isopropanol, a ketone selected from the group consisting of acetone, methylisobutylketone, and tert- butylmethylketone.
  • mixture of protic solvents particularly alcohol-ketone-water and/or alcohol-alcohol-ketone-water mixture, especially the mixture of C 1 -C 6 alcohols and C 3 -C 6 ketones, give the best results with regard to yield as well as solubility of all agents involved.
  • mixture of alcohols and ketones as solvent further has the advantage that methoxytriphenylmethane which is formed during the deprotection reaction readily precipitates from such solvents, further facilitating the purification of the desired product.
  • the compound of formula (II) is reacted with the any acid like hydrochloric acid, sulfuric acid, hydroxyammonium chloride and sulfate or ammonium salts at a temperature from 20 to 40 0 C, preferably from 20 to 25 0 C.
  • the compound of formula (II) is reacted with the acids for 1.0 to 4.5 hours, preferably for 1,5 to 3.5 hours.
  • a trityl-protected biphenyl-tetrazole compounds of the formula (II) is stirred together with one to four equivalent of mineral acid or ammonium salts in a mixture of methanol/ketone mixture in the presence of little amount of water at 20-40 0 C.
  • the progress of the reaction is monitored by HPLC and/or TLC.
  • the stirring is stopped:
  • the formed methoxytriphenylmethane is removed by filtration.
  • the pH of the solution is raised by addition of base to a value of 3.5 to 12.5 depending on the molecule.
  • the mixture is concentrated under reduced pressure.
  • a 2 1 3 -necked flask equipped with a reflux condenser and thermometer was charged with 380 g of methanol, 12O g of trityl- losartan, 95 g of acetone, and 38.4 g of hydrochloric acid (31 %) at room temperature. The mixture was stirred for 2 hours at this temperature.
  • the mixture was analyzed by HPLC. The analysis showed that 99.2 of trityl protected losartan had been consumed.
  • the resulting slurry was filtered and the filter cake containing precipitated methoxytriphenylmethane was washed with 20 g of methanol and sucked to dryness. Wet methoxytriphenylmethane (73 g) were obtained.
  • the pH of the mixture was adjusted to 3.8-4.2 by adding 50% NaOH solution with external cooling to keep the temperature between 20-25 0 C. The mixture was concentrated under reduced pressure.
  • losartan 80 g of water was added, the mixture was stirred for 1 hour at room temperature and crude losartan was isolated by filtration. Crude losartan was suspended into 290 g of ethyl acetate and the mixture was stirred for 1 hour at 25 to 30 0 C. A homogeneous precipitate was obtained, filtered and washed with 20 g ethyl acetate. After drying losartan (70.5 g ) was obtained as a white powder (93 % yield).
  • losartan 80 g of water was added, the mixture was stirred for 1 hour at room temperature and crude losartan was isolated by filtration. Crude losartan was suspended into 290 g of ethyl acetate and the mixture was stirred for 1 hour at 25 to 30 0 C. A homogeneous precipitate was obtained, filtered and washed with 20 g ethyl acetate. After drying losartan (69.2 g) was obtained as a white powder (91.3 % yield).
  • irbesartan To remove the salt and precipitate irbesartan, 80 g of water was added and the mixture was stirred for 1 hour at room temperature. Crude irbesartan was suspended into 290 g of ethyl acetate and the mixture was stirred for 1 hour at 25 to 30 0 C. A homogeneous precipitate was obtained, filtered and washed with 20 g ethyl acetate. After drying irbesartan ( 72 g ) was obtained as a white powder (95% yield).
  • a 2 1 3 -necked flask equipped with a reflux condenser and thermometer was charged with 300 g of methanol, 80 g of isoprapanol, 12O g of trityl- irbesartan, 95 g of acetone, 12 g of water, and 28.8 g of hydroxylammonium chloride at room temperature.
  • the mixture was stirred for 2 hours at this temperature.
  • the mixture was analyzed by HPLC. The analysis showed that 99.5 of trityl protected irbesartan had been consumed.
  • the resulting slurry was filtered and the filter cake containing precipitated methoxytriphenylmethane was washed with 20 g methanol and sucked to dryness. Wet methoxytriphenylmethane (70 g) were obtained.
  • the pH of the mixture was adjusted to 12.0-12.5 by adding 50% NaOH solution with external cooling to keep the temperature between 20-25 0 C and then concentrated under reduced pressure

Landscapes

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

Abstract

Procédé de fabrication de composés du biphényl-tétrazole sous forme pure par déprotection de composés de formule (II) suivante : Le procédé selon l’invention propose l’utilisation d’acides dans un mélange alcool-cétone-eau et/ou un mélange alcool-alcool-cétone-eau pour retirer le groupement protecteur Ph3C.
PCT/TR2006/000007 2005-03-16 2006-03-15 Procede de fabrication de composes du biphenyl-tetrazole Ceased WO2006098705A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06717222A EP2001869A1 (fr) 2005-03-16 2006-03-15 Procede de fabrication de composes du biphenyl-tetrazole

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EPPCT/EP05/002774 2005-03-16
PCT/EP2005/002774 WO2006097121A1 (fr) 2005-03-16 2005-03-16 Procede de preparation de composes biphenyltetrazole

Publications (1)

Publication Number Publication Date
WO2006098705A1 true WO2006098705A1 (fr) 2006-09-21

Family

ID=35432090

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 Before (1)

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

Country Status (1)

Country Link
WO (2) WO2006097121A1 (fr)

Families Citing this family (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 (6)

* 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
WO2003093262A2 (fr) * 2002-04-29 2003-11-13 Teva Pharmaceutical Industries Ltd. Procede de preparation de losartan et de losartan potassium
WO2004007482A2 (fr) * 2002-07-16 2004-01-22 Teva Pharmaceutical Industries Ltd. Nouveau procede de synthese d'irbesartan
US20040224998A1 (en) * 2003-05-06 2004-11-11 Ashok Kumar Losartan potassium synthesis
WO2005111021A1 (fr) * 2004-05-05 2005-11-24 Teva Pharmaceutical Industries Ltd. Elaboration de of candesartan cilexetil de purete elevee
WO2006050922A1 (fr) * 2004-11-11 2006-05-18 Lek Pharmaceuticals D.D. Procede pour la synthese de tetrazoles

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10138955A1 (de) * 2001-08-03 2003-02-20 Aesculap Ag & Co Kg Chirurgisches Instrument zum Platzieren eines Harninkontinenzbandes im Unterleib von Patienten

Patent Citations (6)

* 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
WO2003093262A2 (fr) * 2002-04-29 2003-11-13 Teva Pharmaceutical Industries Ltd. Procede de preparation de losartan et de losartan potassium
WO2004007482A2 (fr) * 2002-07-16 2004-01-22 Teva Pharmaceutical Industries Ltd. Nouveau procede de synthese d'irbesartan
US20040224998A1 (en) * 2003-05-06 2004-11-11 Ashok Kumar Losartan potassium synthesis
WO2005111021A1 (fr) * 2004-05-05 2005-11-24 Teva Pharmaceutical Industries Ltd. Elaboration de of candesartan cilexetil de purete elevee
WO2006050922A1 (fr) * 2004-11-11 2006-05-18 Lek Pharmaceuticals D.D. Procede pour la synthese de tetrazoles

Also Published As

Publication number Publication date
WO2006097121A1 (fr) 2006-09-21

Similar Documents

Publication Publication Date Title
CA2707334C (fr) Procede de preparation ou de purification de l'olmesartan medoxomil
WO2012088607A1 (fr) Procédé pour la préparation d'un sel de tréprostinil
EP1658281B1 (fr) Procede d'extraction du groupe protecteur de triphenylmethane
EP2723709B1 (fr) Fabrication d'un produit de contraste triiodé
EP1274702B1 (fr) Procede de synthese d'un derive connu du tetrazol
JP2004520446A (ja) ロサルタンカリウムの結晶化方法
EP2608791B1 (fr) Procédé pour la préparation d'imatinib base
JP5289331B2 (ja) ４−アミノ−ピリミジンの合成
EP3881848B1 (fr) Procédé de production d'un dérivé d'acide orotique
HU229188B1 (hu) Új eljárás N-[(S)-1-karboxibutil]-(S)-alanin-észterek elõállítására, és a perindopril szintézisnél történõ alkalmazása
EP1533305B1 (fr) Procédé de préparation du Valsartan
WO2006098705A1 (fr) Procede de fabrication de composes du biphenyl-tetrazole
EP2001869A1 (fr) Procede de fabrication de composes du biphenyl-tetrazole
EP2016073B1 (fr) Procede de preparation d'irbesartan pur
WO2012103105A1 (fr) Procédés de préparation du raltégravir et de ses intermédiaires dans lesdits procédés
KR100662110B1 (ko) 테트라졸 유도체의 제조방법
JPH072742A (ja) ４−アミノ−３−メチル−Ｎ−エチル−Ｎ−（β−ヒドロキシエチル）アニリン硫酸塩の新規製造法
EP0621260B1 (fr) Procédé pour la préparation d'un dérivé de la p-phénylènediamine sulfate N,N-disubstituiertes p-Phenylendiamine sulfat-Derivate
EP1963309B1 (fr) Procédé de production de sels métalliques de losartan
WO2008018843A1 (fr) Procédé de production de formes de sel utiles de composés de biphényl-tétrazole
EP2022790A1 (fr) Procédé pour la préparation ou la purification d'olmésartan médoxomil
KR100701420B1 (ko) 비페닐테트라졸 유도체의 제조방법
CN120943782A (zh) 一种吡唑醚类化合物的制备方法
JPH10310568A (ja) Ｎ−アルコキシカルボニル−ｌ−アスパラギン
JP4739695B2 (ja) ５−アミノ―１―置換―１，２，４―トリアゾールの製造方法、及び該製造方法で得られるトリアゾール誘導体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

WWE Wipo information: entry into national phase

Ref document number: 2006717222

Country of ref document: EP