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WO2003066565A1 - Derives biphenyle deuterises - Google Patents

Derives biphenyle deuterises Download PDF

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Publication number
WO2003066565A1
WO2003066565A1 PCT/DE2003/000367 DE0300367W WO03066565A1 WO 2003066565 A1 WO2003066565 A1 WO 2003066565A1 DE 0300367 W DE0300367 W DE 0300367W WO 03066565 A1 WO03066565 A1 WO 03066565A1
Authority
WO
WIPO (PCT)
Prior art keywords
trideuteromethyl
deuterated
biphenyl
tetrazole
group
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/DE2003/000367
Other languages
German (de)
English (en)
Inventor
Rudolf-Giesbert Alken
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.)
TURICUM DRUG DEVELOPMENT AG
Original Assignee
TURICUM DRUG DEVELOPMENT AG
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 TURICUM DRUG DEVELOPMENT AG filed Critical TURICUM DRUG DEVELOPMENT AG
Priority to AU2003227005A priority Critical patent/AU2003227005A1/en
Publication of WO2003066565A1 publication Critical patent/WO2003066565A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/33—Polycyclic acids
    • C07C63/331—Polycyclic acids with all carboxyl groups bound to non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D263/12—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention relates to deuterated biphenyl derivatives and deuterated precursors for the preparation of these compounds.
  • Deuterated biphenyl derivatives are important intermediates for the synthesis of drugs, in particular the so-called “- sartans", which can be used, for example, for the treatment of circulatory disorders, high blood pressure and heart diseases.
  • the Ullmann reaction can be used to produce symmetrically and asymmetrically substituted biphenyls.
  • halogen aryl compounds preferably iodine compounds, are used in the presence of copper at high
  • the object of the present invention is therefore to provide deuterated biphenyl derivatives which can be used in particular in the manufacture of deuterated medicaments.
  • R 1 is independently of one another H or D
  • R 2 is C-C3-al yl or Ci-Cs-alkyl substituted by one or more halogen atoms, hydroxy groups, sulfhydroxy groups, phosphate groups or sulfate groups, which can be partially or completely deuterated
  • R 3 is a carboxyl or deuterated carboxyl group, a carbamide or deuterated carbamide group, a cyano group, an oxazoline group, a tetrazole group, a deuterated tetrazole group, a substituted tetrazole group, N- (trimethylstannyl) pyrazole group, a deuterated N- (trimethylstannyl) ) pyrazole group, a pyrazole group, a deuterated pyrazole group or a pyrazole group substituted with a triphenylmethyl group or with a deuterated triphenylmethyl group, these groups in turn being substituted by one or more C 1 -C 3 -alkyl groups, halogen atoms, hydroxyl groups, sulfhydroxy groups, phosphate groups or sulfate groups -Ca-alkyl, which can be partially or completely deuterated and wherein at least one of the radicals R 1 to
  • Deuterated biphenyl derivatives of the general formula I in which R 1 is independently H or D, R 2 is trideuteromethyl and R 3 is a carbamide group or a deuterated carbamide group are particularly preferred.
  • Deuterated biphenyl derivatives of the general formula I in which R 1 is independently H or D, R 2 is trideuteromethyl and R 3 is an N- (trimethylstannyl) pyrazole group are particularly preferred.
  • Deuterated biphenyl derivatives of the general formula I in which R 1 is independently H or D, R 2 is trideuteromethyl and R 3 is a pyrazole group or a deuterated pyrazole group are advantageous.
  • Deuterated biphenyl derivatives of the general formula I in which R 1 is independently H or D, R 2 is trideuteromethyl and R 3 is a pyrazole group which is substituted by a triphenylmethyl group are particularly advantageous.
  • Deuterated biphenyl derivatives of the general formula I in which R 1 is independent of one another H or D, R 2 is a bromideideuteromethyl group are particularly advantageous and R 3 represents a pyrazole group substituted by a triphenylmethyl group.
  • the object of the invention is achieved by the provision of
  • the deuterated acid chloride is generated and this is reacted with 2-amino-2-methyl-l-propanol to give the deuterated 4,4-dimethyl-2- (2-methoxyphenyl) oxazoline.
  • This oxazoline is further processed with deuterated 4-methylphenyl-Grignard reagent, obtained from deuterated 4-bromotoluene, to give deuterated 2- (4'-methylbiphenyl-2-yl) -4, 4-dimethyloxazoline.
  • deuterated 4'-methyl-2-biphenylcarboxylic acid is obtained from this by heating in deuterium chloride solution.
  • the deuterated 4'-methyl-2-biphenylcarboxylic acid is converted to deuterated 4'-methyl-2-biphenylnitrile via the acid amide which is obtained from the acid chloride with ammonium hydroxide solution.
  • Methyl 2-biphenyl nitrile with trimethyltin azide obtained N-trimethylstannyl-5- (4'-methylbiphenyl-2-yl) etrazole.
  • the tetrazole group is subsequently protected by reaction with trityl chloride and the deuterated N-triphenylmethyl-5- (4'-methylbiphenyl-2-yl) tetrazole obtained is converted into the deuterated (bromomethyl) biphenyl derivative with N-bromosuccinimide.
  • the product is prepared by dissolving 33 g of N-trimethylstannyl-5- (dll-4 '- methylbiphenyl-2-yl) tetrazole in a mixture of toluene and tetrahydrofuran and so long dry deuterium chloride at room temperature through the solution is blown until a clear solution is obtained.
  • the product crystallizes out of the solution and is obtained

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des dérivés biphényle déutérisés ainsi que des précurseurs déutérisés pour la production de ces composés. Les dérivés biphényle déutérisés constituent des produits intermédiaires importants dans la synthèse de médicaments qui peuvent être utilisés, par exemple, pour le traitement de troubles de la circulation, de l'hypertension et de maladies cardiaques.
PCT/DE2003/000367 2002-02-07 2003-02-06 Derives biphenyle deuterises Ceased WO2003066565A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003227005A AU2003227005A1 (en) 2002-02-07 2003-02-06 Deuterated biphenyl derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10205336A DE10205336A1 (de) 2002-02-07 2002-02-07 Deuterierte Biphenylderivate
DE10205336.7 2002-02-07

Publications (1)

Publication Number Publication Date
WO2003066565A1 true WO2003066565A1 (fr) 2003-08-14

Family

ID=27618480

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE2003/000367 Ceased WO2003066565A1 (fr) 2002-02-07 2003-02-06 Derives biphenyle deuterises

Country Status (3)

Country Link
AU (1) AU2003227005A1 (fr)
DE (1) DE10205336A1 (fr)
WO (1) WO2003066565A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7674796B2 (en) 2002-12-20 2010-03-09 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0291969A2 (fr) * 1987-05-22 1988-11-23 E.I. Du Pont De Nemours And Company Dérivés de tétrazole comme produits intermédiaires pour composés anti-hypertensifs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0291969A2 (fr) * 1987-05-22 1988-11-23 E.I. Du Pont De Nemours And Company Dérivés de tétrazole comme produits intermédiaires pour composés anti-hypertensifs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CARINI D J ET AL: "NONPEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS: THE DISCOVERY OF A SERIES OF N-(BIPHENYLYLMETHYL)IMIDAZOLES AS POTENT, ORALLY ACTIVE ANTIHYPERTENSIVES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 34, no. 8, 1 August 1991 (1991-08-01), pages 2525 - 2547, XP000674205, ISSN: 0022-2623 *
DUNCIA, J.V. ET AL.: "Three synthetic routes to a sterically hindered tetrazole. A new one-step mild conversion of an amide into a tetrazole", J. ORG. CHEM., vol. 56, 1991, pages 2395 - 2400, XP002243982 *
MANTLO N B ET AL: "POTENT, ORALLY ACTIVE IMIDAZOU4,5-BPYRIDINE-BASED ANGIOTENSIN II RECEPTOR ANTAGONISTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 34, no. 9, 1 September 1991 (1991-09-01), pages 2919 - 2922, XP000674665, ISSN: 0022-2623 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7674796B2 (en) 2002-12-20 2010-03-09 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
US7741336B2 (en) 2002-12-20 2010-06-22 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth

Also Published As

Publication number Publication date
DE10205336A1 (de) 2003-08-21
AU2003227005A1 (en) 2003-09-02

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