EP1546104A1 - Verfahren zur herstellung von pyridyl-arylsulfonsäure derivate - Google Patents

Verfahren zur herstellung von pyridyl-arylsulfonsäure derivate

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Publication number
EP1546104A1
EP1546104A1 EP02785894A EP02785894A EP1546104A1 EP 1546104 A1 EP1546104 A1 EP 1546104A1 EP 02785894 A EP02785894 A EP 02785894A EP 02785894 A EP02785894 A EP 02785894A EP 1546104 A1 EP1546104 A1 EP 1546104A1
Authority
EP
European Patent Office
Prior art keywords
moles
compound
phosphines
palladium
alkyl
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.)
Withdrawn
Application number
EP02785894A
Other languages
English (en)
French (fr)
Inventor
Maurizio Paiocchi
Francesco Ponzini
Marco Nicolini
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.)
Archimica SpA
Original Assignee
Euticals Prime European Therapeuticals SpA
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 Euticals Prime European Therapeuticals SpA filed Critical Euticals Prime European Therapeuticals SpA
Publication of EP1546104A1 publication Critical patent/EP1546104A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C07D213/34—Sulfur atoms to which a second hetero atom is attached

Definitions

  • the subject of the present invention is the preparation of compounds of formula 1 :
  • Z represents I, Br, Cl, triflate, sulphonate and/or sulphone
  • Ri, R 2 , R 4 , R 5 which are the same as one another or different, represent H, a linear and/or branched C ⁇ -C alkyl, and/or an aryl, and/or a heteroaryl, or Ri and R 2 and/or R and R5, taken together, form a C 3 -C 8 ring, an aryl and/or a heteroaryl, and
  • R3 represents a linear, branched or cyclic C ⁇ -C 8 alkyl and/or an aryl, and/or a heteroaryl.
  • the compounds of formula 1 are intermediates usable for the synthesis of various classes of active ingredients such as, for example: anti-inflammatories (WO 96/24584 and W096/24585), metalloproteinase inhibitors (WO 99/26909), anti- hypercholesteraemics, anti-hyperlipoproteinaemics, and anti-allergies (WO 98/04528), 2-cyclooxigenase inhibitors (WO 99/14195, WO 99/59635 and WO 00/38716), anti-arrythmics (EP-699666) and antibacterials (EP-481662), which are incorporated herein by reference.
  • the compound of formula 2 is an anti-inflammatories (WO 96/24584 and W096/24585), metalloproteinase inhibitors (WO 99/26909), anti-
  • the compound of formula 2 is normally prepared by a coupling reaction between 3-pyridyldiethyl borane and 3-bromophenylmethyl sulphone in THF, catalyzed by palladium tetrakistriphenyl phosphine in the presence of potassium hydroxide and tetrabutylammonium iodide (Sonesson, C. et al. T.L.
  • a second disadvantage relates to the behaviour of the sulphone groups when they are subjected to the cross-coupling conditions; in fact several cases are known in the literature in which aryl-sulphonic and alkyl-sulphonic groups behave as leaving groups in cross-coupling reactions, thus promoting undesired competitive reactions (Julia M, et al, / Perk, Trans. 95, 7; Wenckert, E. et & ⁇ ]CS Chem. Comm. 79, 637; German patent application DE 196 36 995 Al).
  • Z represents I, Br, Cl, trifiate, sulphonate and/or sulphone
  • Ri, R 2 , R 4 , R5 which are the same as one another or different, represent H, a linear and/or branched C ⁇ -C alkyl, and/or an aryl, and/or a heteroaryl, or Ri and R 2 and/or R 4 and R5, taken together, form a C 3 -C 8 ring, an aryl and/or a heteroaryl, and
  • R3 represents a linear, branched or cyclic C ⁇ -C 8 alkyl and/or an aryl, and/or a heteroaryl.
  • Palladium and nickel are normally used in quantities of 0.01-10 moles, preferably 0.05-2 moles, per 100 moles of compound 3; the reaction is normally carried out by adding an organic solution of compound 3 to an organic solution containing compound 4 and the catalytic system.
  • the organic solvent is preferably an ethereal solvent (such as, for example, not to react with the Grignard compounds) such as THF, 1,2 dimethoxyethane, and/or 1,1- diethoxymethane; the reaction is carried out at a temperature of between 20 and 80°C, preferably between 40 and 60°C.
  • an ethereal solvent such as, for example, not to react with the Grignard compounds
  • THF 1,2 dimethoxyethane
  • 1,1- diethoxymethane 1,1- diethoxymethane
  • the reaction yield can be increased by operating in the presence of phosphines and/or phosphites, to be used preferably in a molar ratio of catalystphosphine/phosphite of between 1:1 and 1:6.
  • the phosphines usable for the purposes of the present invention may be: triaryl phosphines, such as triphenyl phosphine, tritolyl phosphine, trixylyl phosphine, tri-2-furyl phosphine; diaryl alkylphosphines, such as methyldiphenyl phosphine, benzyldiphenyl phosphine, cyclohexyldiphenyl phosphine; dialkylaryl phosphines, such as 2-(di-t- butylphosphino)- biphenyl, 2-(dicyclohexylphosphino)biphenyl; trialkyl phosphines
  • Palladium is generally added to the reaction medium in the form of complexes with phosphines such as, for example, palladium tetrakistriphenyl phosphine (Pd(PPh 3 ) 4 ) or as palladium salt, generally acetate or chloride, and a phosphine, preferably triphenyl phosphine; normally, one mole of palladium acetate or chloride is used in combination with 4 moles of triphenyl phosphine (Pd(OAc) 2 or PdCl 2 + 4PPh 3 ).
  • phosphines such as, for example, palladium tetrakistriphenyl phosphine (Pd(PPh 3 ) 4 ) or as palladium salt, generally acetate or chloride, and a phosphine, preferably triphenyl phosphine; normally, one mole of palladium acetate or chloride is used in combination with 4 moles of
  • nickel is normally used in the form of complexes with phosphines, preferably bidentate phosphines, such as, for example, 1,3- bis(diphenylphosphino)propane (dppp) or l,4-bis(diphenylphosphino)butane (dppb); these complexes are added to the reaction solution as salts such as, for example, Ni(dppp)Cl 2 or Ni(dppb)Cl 2 .
  • phosphines preferably bidentate phosphines, such as, for example, 1,3- bis(diphenylphosphino)propane (dppp) or l,4-bis(diphenylphosphino)butane (dppb); these complexes are added to the reaction solution as salts such as, for example, Ni(dppp)Cl 2 or Ni(dppb)Cl 2 .
  • the reaction may also be carried out in the presence of zinc salts such as, for example, zinc chloride (ZnCl 2 ), zinc bromide (ZnBr 2 ) and zinc acetate (Zn(OAc) 2 ); the zinc salt is normally used in quantities of 25-120 moles, preferably 35-70 moles, per 100 moles of compound 3.
  • zinc salts such as, for example, zinc chloride (ZnCl 2 ), zinc bromide (ZnBr 2 ) and zinc acetate (Zn(OAc) 2 );
  • Zn(OAc) 2 zinc acetate
  • the reaction according to the present invention may also be carried out both in the presence of alkyl halides (up to quantities greater than that which is equtmolar with the Grignard), and in the presence of variable quantities of alkyl Grignard; this result is particularly surprising if it is borne in mind that, in identical reaction conditions (Example 9), alkyl Grignards provide the product of homocoupling of the sulphonic derivative with yields greater than 60%, as illustrated in the following scheme:
  • Example 1 Grignard A by reaction of a halogeno(bromo, iodo)-pyridine with a catalytic quantity of alkyl halide in the presence of an at least stoichiometric quantity of magnesium;
  • the alkyl halide is normally a C ⁇ -C 8 alkyl chloride or bromide, preferably ethyl bromide or isopropyl bromide or chloride.
  • halogeno-pyridine is reacted with 10-20 moles of alkyl halide and 100-120 moles of magnesium.
  • the reaction is generally carried out at a temperature of 0-60°C, preferably at 15-35°C, in an aprotic organic solvent which does not react with a Grignard reagent, preferably in tetrahydrofuran or mixtures of tetrahydrofuran and toluene; the solution thus obtained is then added dropwise to the solution containing compound 4 and the catalytic system.
  • a Grignard reagent preferably in tetrahydrofuran or mixtures of tetrahydrofuran and toluene
  • 3-bromophenylmethyl sulphone (19.5 g, 0.0825 moles) and palladium tetrakistriphenyl phosphine (0.095 g, 0.082 moles) were added to a mixture of anhydrous ZnCl 2 (4.0g, 0.0293 moles) in anhydrous tetrahydrofuran (45.0 g), kept at 50°C, with mechanical stirring, in an inert atmosphere.
  • Grignard A solution (79.5 g) was added to the resulting suspension over 3 hours, still at 50°C. The reaction mixture was stirred for 1 hour.
  • the mixture was cooled to 25°C, treated with 120 g of 10% w/w hydrochloric acid solution and the phases were separated.
  • the aqueous phase was treated with 70g of a 28% w/w ammonia solution, toluene was added, and the phases were separated.
  • the toluene phase was evaporated to oil at reduced pressure. Crystallization from 96g of isopropyl alcohol was then performed. 15.4 g of 3-(3'pyridyl)phenylmethyl sulphone (0.066 moles; yield 80% relative to 3-bromophenylmethyl sulphone) was obtained.
  • M.P. 86°C
  • 3-bromophenylmethyl sulphone (19.5 g, 0.0825 moles) and palladium tetrakistriphenyl phosphine (0.095 g, 0.082 mmoles) were added to a mixture of anhydrous ZnCl 2 (12.0 g 0.088 moles) in anhydrous tetrahydrofuran (45.0 g), kept at
  • 2-propyl magnesium chloride (2M in tetrahydrofuran, 0.045 g, 0.9 mmoles, Aldrich cat. 2000/2001) was added over 5' to a suspension of Ni(dppp)Cl 2 (0.231 g, 0.42 mmoles) in anhydrous tetrahydrofuran (3.5g), cooled to 0°C, in a 10 ml flask kept under inert atmosphere and with magnetic stirring. The temperature was allowed to rise to 20°C and stirring was continued for 10'.
  • the catalyst solution was added to a solution of 3-bromophenylmethyl sulphone (9.9 g, 0.042 moles) in anhydrous tetrahydrofuran (18.0 g), kept at 50°C, with mechanical stirring, in an inert atmosphere.
  • Grignard A solution (44.0 g) was added over 4 hours. The reaction mixture was stirred for 1 hour and then cooled to 25°C.
  • 2-propyl magnesium chloride (2M in tetrahydrofuran, 0.045 g, 0.9 mmoles Aldrich cat. 2000/2001) was added over 5' to a suspension of anhydrous NiCl 2 (0.055 g, 0.42 mmoles) and triphenyl phosphine (0.22 g, 0.84 mmoles) in anhydrous tetrahydrofuran (3.5 g), cooled to 0°C, in a 10 ml flask kept under an inert atmosphere and with magnetic stirring. The temperature was allowed to rise to 20°C and stirring was continued for 10'.
  • the catalyst solution was added to a solution of 3-bromophenylmethyl sulphone (9.9 g, 0.042 moles) in anhydrous tetrahydrofuran (18.0 g), kept at 50°C with mechanical stirring, in an inert atmosphere.
  • Grignard A solution (44.0 g) was added over 4 hours. The reaction mixture was stirred for 1 hour and then cooled to 25°C.
  • 2-propyl magnesium chloride (2M in tetrahydrofuran, 0.045 g, 0.9 mmoles, Aldrich cat. 2000/2001) was added over 5' to a suspension of anhydrous NiCl 2 (0.055 g, 0.42 mmoles) and triphenyl phosphine (0.22 g, 0.84 mmoles) in anhydrous tetrahydrofuran (3.5 g), cooled to 0°C, in a 10 ml flask kept under inert atmosphere and with magnetic stirring. The temperature was allowed to rise to 20°C and stirring was continued for 10'.
  • the catalyst solution was added to a mixture constituted by anhydrous zinc chloride
  • 3-bromophenylmethyl sulphone (19.5 g, 0.0825 moles) and palladium tetrakistriphenyl phosphine (0.095 g, 0.082 mmoles) were added to a mixture of anhydrous ZnCl 2 (4.0 g, 0.0293 moles) in anhydrous tetrahydrofuran (45.0 g), kept at

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP02785894A 2002-10-02 2002-10-02 Verfahren zur herstellung von pyridyl-arylsulfonsäure derivate Withdrawn EP1546104A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IT2002/000626 WO2004039779A1 (en) 2002-10-02 2002-10-02 Process for the preparation of pyridyl-aryl-sulphonic compounds

Publications (1)

Publication Number Publication Date
EP1546104A1 true EP1546104A1 (de) 2005-06-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP02785894A Withdrawn EP1546104A1 (de) 2002-10-02 2002-10-02 Verfahren zur herstellung von pyridyl-arylsulfonsäure derivate

Country Status (3)

Country Link
EP (1) EP1546104A1 (de)
AU (1) AU2002349815A1 (de)
WO (1) WO2004039779A1 (de)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19500760A1 (de) * 1995-01-13 1996-07-18 Basf Ag Substituierte 2-Phenylpyridine
DE19636995A1 (de) * 1996-09-12 1998-03-19 Basf Ag Verfahren zur Herstellung substituierter Phenylpyridine
DE19831246A1 (de) * 1998-07-11 2000-01-13 Clariant Gmbh Verfahren zur Herstellung von Arylpyridinen
IT1313664B1 (it) * 1999-10-12 2002-09-09 Norpharma S P A Processo per la preparazione di un composto aril-piridinico.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004039779A1 *

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Publication number Publication date
AU2002349815A1 (en) 2004-05-25
WO2004039779A1 (en) 2004-05-13

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