EP2111404A1 - Verfahren zur herstellung arylsubstituierter anellierter pyrimidine - Google Patents

Verfahren zur herstellung arylsubstituierter anellierter pyrimidine

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Publication number
EP2111404A1
EP2111404A1 EP08701400A EP08701400A EP2111404A1 EP 2111404 A1 EP2111404 A1 EP 2111404A1 EP 08701400 A EP08701400 A EP 08701400A EP 08701400 A EP08701400 A EP 08701400A EP 2111404 A1 EP2111404 A1 EP 2111404A1
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Prior art keywords
reaction
sub
formula
sup
compounds
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EP08701400A
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German (de)
English (en)
French (fr)
Inventor
Bernd Wolf
Volker Maywald
Michael Keil
Manuel Budich
Michael Rack
Manfred Ehresmann
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BASF SE
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BASF SE
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Priority to EP08701400A priority Critical patent/EP2111404A1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to processes for preparing aryl-substituted fused pyrimidines comprising reacting a 2-phenylmalonate in the presence of a suitable base and a heterocyclic amine, and reacting the dihydroxy-substituted compounds thus obtained with a halogenating agent.
  • Aryl-substituted fused pyrimidines specifically 5,7-dihalo and 5,7-dihydroxy-6-aryl-1,2,4-triazolo [1,5-a] pyrimidines, are useful building blocks for the preparation of a variety of agrochemical and pharmaceutical compounds.
  • these key building blocks in the synthesis of fungicidal Triazolopyrimidinderivate as described for example in EP 0 550 113, EP 0 782 997, EP 0 770 615 or WO 98/46607.
  • EP 0 550 113 and EP 0 782 997 describe the preparation of 6-aryl-5,7-dihalo-1, 2,4-triazolo [1, 5-a] pyrimidines of the following formula
  • the 5,7-dihydroxy-substituted 1,2,4-triazolo [1,5-a] pyrimidines are provided starting from malonic acid esters and 3-amino-1,2,4-triazole.
  • EP 0 770 615 describes processes for the preparation of 5,7-dihalo-1, 2,4-triazolo [1, 5-a] pyrimidines and 5,7-dihaloimidazopyrimidines, wherein in a first step a malonic acid ester with a heterocyclic amine is reacted at a temperature of at least 100 0 C.
  • the resulting 5,7-dihydroxy-substituted triazolo or imidazopyrimidines or their intermediately formed salts are at a temperature of at least 100 0 C with at least two equivalents of a halogenating agent to the 5,7-dihalo-1, 2,4-triazolo [ 1, 5-a] pyrimidines or 5,7-dihaloimidazopyrimidines reacted.
  • the processes known in the art for preparing aryl-substituted fused pyrimidines are not fully satisfactory in terms of the available yields and product purities.
  • the object underlying the present invention is therefore to provide a process which provides aryl-substituted fused pyrimidines in high yield and purity.
  • the present invention therefore provides a process for the preparation of aryl-substituted fused pyrimidines of the general formula (I)
  • L 1 , L 2 , L 3 , L 4 and L 5 independently of one another represent hydrogen, halogen, cyano, nitro,
  • Ci-C 4 -alkyl Ci-C 4 haloalkyl, Ci-C4-alkoxy, Ci-C2 haloalkoxy, Ci-C4 alkyl carbonyl, Ci-C4-haloalkylcarbonyl, Ci-C 4 alkoxycarbonyl, C C 4 alkylamino carbonyl or di (Ci-C 4 alkyl) aminocarbonyl and
  • Y 1 , Y 2 , Y 3 independently represent CR ⁇ or N.
  • substituents R ⁇ are independently selected from hydrogen and optionally mono- or polysubstituted by halogen, cyano, nitro, Ci-C 4 alkoxy, Ci-C2-haloalkoxy, Ci-C 4 alkylaminocarbonyl or di (Ci-C 4- alkyl) - aminocarbonyl-substituted C 1 -C 4 -alkyl; or
  • R is C 1 -C 8 -alkyl and the substituents L 1 , L 2 , L 3 , L 4 and L 5 have one of the meanings given above,
  • step (ii) reacting the compounds of formula (I) obtained in step (i) wherein X is OH or the salts with a halogenating agent.
  • halogen denotes in each case fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine, in particular fluorine.
  • C 1 -C 4 -alkyl as used herein and in the terms C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylaminocarbonyl and di (C 1 -C 4 -alkyl) aminocarbonyl, denotes a saturated, straight-chain or branched hydrocarbon group, comprising 1 to 4 carbon atoms, for example ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1, 1-dimethylethyl.
  • C 1 -C 4 haloalkyl as used herein and in the haloalkyl moieties of C 1 -C 4 haloalkoxy and C 1 -C 4 haloalkylcarbonyl describes straight-chain or branched alkyl groups having from 1 to 4 carbon atoms, the hydrogen atoms of these groups being partly or completely Halogen atoms, for example C 1 -C 4 -haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2- Fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,
  • C 1 -C 4 alkoxy as used herein describes straight-chain or branched saturated alkyl groups comprising 1 to 4 carbon atoms which are bonded via an oxygen atom.
  • Examples of C 1 -C 4 -alkoxy include, for example, methoxy, ethoxy, OCH 2 -C 2 H 5 , OCH (CH 2 ) 2 , n-butoxy, OCH (CH 2 ) 5 -C 2 H 5 , OCH 2 -CH (CH 2 ) 2 , OC (CHs) 3 .
  • C 1 -C 4 -haloalkoxy describes C 1 -C 4 -alkoxy groups as described above, wherein the hydrogen atoms of these groups are partially or completely replaced by halogen atoms, ie, for example, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, Difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2- Chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, 2-
  • salts of the compounds of the general formula (I) is used in the context of the present invention for the aggregation products of the compounds of the formula (I) with the bases used in step (i) and optionally for the aggregation products of mono- or polysubstituted deprotonated compounds of the formula (I) with the respective cationic portion of the bases used in step (i).
  • 1, 2 or 3 of the substituents L 1 , L 2 , L 3 , L 4 and L 5 in the compounds of the general formulas (I) and (II) are different from hydrogen.
  • at least the substituent L 1 is different from hydrogen.
  • the substituents L 1 , L 2 , L 3 , L 4 and L 5 in the compounds of the general formulas (I) and (II) are independently selected from hydrogen, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 2 -haloalkoxy.
  • the substituents L 1 , L 2 , L 3 , L 4 and L 5 in the compounds of the general formulas (I) and (II) are independently selected from hydrogen, halogen, C 1 -C 4 -alkyl and C 1 -C 4 alkoxy.
  • the substituents L 1 , L 2 , L 3 , L 4 and L 5 are particularly preferably selected from hydrogen, fluorine, chlorine, bromine, methyl or methoxy. Most preferably, the substituents L 1 , L 2 , L 3 , L 4 and L 5 are selected from hydrogen, fluorine, chlorine or bromine.
  • L 1 , L 3 and L 5 are fluorine and L 2 and L 4 are hydrogen.
  • the heterocyclic compounds of the formula (III) can be used in the form represented by the formula, in the form of tautomers of these compounds or in the form of tautomer mixtures.
  • the compounds of the formula (III) are frequently also in the form of the tautomers, as in the following scheme using the example of compounds in which Y 1 stands for N, is shown.
  • a preferred embodiment relates to a process for preparing a compound of formula (I) wherein Y 1 in the compounds of general formula (III) and in their tautomers is N and Y 2 and Y 3 are selected from N and CH. Accordingly, a specific embodiment relates to a method in which Compounds of general formula (III) Y 1 and Y 3 are N and Y 2 is CH. Another specific embodiment relates to a process wherein in the compounds of general formula (III) Y 1 is N and Y 2 and Y 3 are CH.
  • suitable compounds of the formula (III) are 1H-pyrrol-2-amine, 1H-imidazol-2-amine, 1H-imidazol-5-amine, 1H-pyrazol-5-amine, 1H-1, 2,3-triazole-5-amine, 4H-1, 2,4-triazol-3-amine, 1H-1, 2,4-triazole-5-amine and the tautomers of these compounds, such as 1H-imidazole 4-amine, 1H-pyrazole-3-amine, 1H-1, 2,3-triazole-4-amine, 2H-1, 2,3-triazole-4-amine and 1H-1, 2,4 triazole-3-amine, wherein the above-mentioned compounds are unsubstituted or may have a substituent different from hydrogen R ⁇ , which is bonded to a carbon atom. In particular, the compounds are unsubstituted.
  • step (i) the heterocyclic compound of the general formula (III)
  • 1, 2,4-triazole-5-amine or its tautomer 1 H-1, 2,4-triazole-3-amine (amitrole) used.
  • 1H-1,2,4-triazole-3-amine very particular preference is given to using 1H-1,2,4-triazole-3-amine.
  • the substituents R Y1 , R Y2 , R Y3 and R Y4 in this particular embodiment are hydrogen.
  • Examples of such compounds of formula (III) are optionally substituted 2-aminoindoles or 2-aminobenzimidazoles.
  • the alcohol of the formula R-OH released during the reaction is a C 1 -C 4 -alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, in particular methanol or ethanol and especially ethanol.
  • the malonic acid esters of the formula (II) are generally used in an amount of 0.5 to 2 molar equivalents, preferably 0.75 to 1.5 molar equivalents, based on one molar equivalent of the compounds of the formula (III). Specifically, the malonic acid esters of the formula (II) are used in about equimolar amounts or in slight excess, based on the compounds of the formula (III), ie 0.9 to 1.05 molar equivalents of the malonic acid ester based on compound (III).
  • the alcohol R-OH released from the reaction in step (i) is removed from the reaction solution under reduced pressure.
  • the alcohol R-OH is substantially completely removed, ie, up to a residual content of at most 2 wt .-%, preferably at most 0.5 wt .-% and particularly preferably at most 0.1 wt .-%.
  • step (i) of the method according to the invention is carried out by supplying thermal energy.
  • the preferred reaction temperature in this step is limited upwards by the boiling points of the compounds of the formulas (II) and (III) used and by the boiling point of the base used at the respective reaction pressure.
  • the reaction temperature is preferably in the range from 40 to 250 ° C., more preferably in the range from 80 to 200 ° C.
  • the reduction of the pressure in step (i) preferably takes place in such a way that over the entire duration of the reaction at most 5%, more preferably at most 2% and especially at most 1% of the amount of the 2-phenylmalonate of the general formula (II) used is common be removed by distillation with the alcohol R-OH.
  • this is achieved in that the pressure in the course of the reaction gradually or in particular continuously over a longer period z. B. 2 to 20 h, in particular 4 to 10 h reduced.
  • the pressure difference is over the entire duration of the reaction 10 to 1000 mbar, in particular 100 to 990 mbar.
  • the pressure is in the range from 700 to 1100 mbar, in particular 800 mbar to ambient pressure, and in the course of the reaction to a pressure in the range from 5 to 300 mbar, in particular in one Range of 10 to 250 mbar, diminished.
  • reaction time and the pressure at which the components of a reaction mixture undergo a change in the state of aggregation depend on the reaction temperature, ie. H. if the reaction temperature is increased, on the one hand, the reaction rate increases; on the other hand, the pressure at which the components of a reaction mixture undergo a change in the state of aggregation decreases; If the reaction temperature is lowered, the rate of reaction is reduced and the pressure at which the components of a reaction mixture undergo a change in the aggregate state is increased. Therefore, a suitable pressure range for step (i) of the process according to the invention is shown below at a given reaction temperature. The skilled person can easily determine the appropriate pressure range at other reaction temperatures by calculation with the aid of the generally known physical laws.
  • reaction pressure For example, at a given reaction temperature of 120 to 160 ° C., it is preferable to continuously or stepwise increase the reaction pressure over a period of 5 to 5 hours 10 h from a value of 1050 to 700 mbar at the beginning of the reaction to a value of 250 to 50 mbar to reduce. Specifically, for example, at a reaction temperature of about 150 0 C, the reaction pressure gradually, hourly reduced from a value of about 800 mbar at the start of the reaction to a value of about 150 mbar over a period of 6 to 8 hours. This ensures almost complete implementation.
  • step (i) the pressure at constant temperature is continuously reduced in step (i).
  • a base is preferably employed whose boiling point at atmospheric pressure of at least 30 0 C, preferably at least 50 0 C and in particular at least 100 0 C above the boiling point of the reaction in step (i) liberated alcohol R-OH is located.
  • Suitable bases used in step (i) are, for example, tertiary amines.
  • tertiary amine in the context of the present invention comprises both tertiary amines which have at least one tertiary nitrogen atom which has three aliphatic or cycloaliphatic substituents which optionally form a mono- or bicyclic ring skeleton with the nitrogen atom, as well as nitrogen compounds,
  • the tertiary amines A usually have 1 or 2 tertiary nitrogen atoms, in particular 1 nitrogen atom.
  • Particularly preferred tertiary amines comprise at least 6, especially at least 8 and especially at least 10 carbon atoms, e.g. B. 6 to 20, in particular 8 to 18 and especially 10 to 16 carbon atoms. These are characterized in particular by a boiling point which is below the reaction pressure given by at least 5 0 C, more preferably at least 10 0 C and most preferably at least 20 0 C above the reaction temperature.
  • tertiary amines of the following general formula NR 1 R 2 R 3 are suitable, wherein R 1 , R 2 and R 3 are independently d-C ⁇ -alkyl, Cö-Cs-cycloalkyl, aryl, the optionally carries one or two C 1 -C 4 -alkyl groups as substituents, or phenyl-C 1 -C 4 -alkyl suitable.
  • the total number of carbon atoms is generally 6 to 20, especially 8 to 18 and especially 10 to 16.
  • tertiary amines are N, N-dimethylcyclohexylamine, tripropylamine, tributylamine, N-ethyl-N-propylaminopropane, N, N- Dimethylaniline and N, N-diethylaniline, especially tributylamine.
  • pyridine compounds are suitable as base in step (i), in particular mono-, di- and tri-C 1 -C 4 -alkylpyridines having preferably together with 6 to 18 C atoms, such as picolines, mono-, di-, tri- (methyl) -pyridines, furthermore phenyl-, pyridyl-, benzyl-, pyridylmethyl- or pyridylethyl-substituted pyridines, furthermore 4-dialkylaminopyridines as well Mono- and di-C 1 -C 4 alkoxypyridines.
  • mono-, di- and tri-C 1 -C 4 -alkylpyridines having preferably together with 6 to 18 C atoms, such as picolines, mono-, di-, tri- (methyl) -pyridines, furthermore phenyl-, pyridyl-, benzyl-, pyridylmethyl- or pyridylethy
  • bridged amines are suitable, d. H. tertiary amines in which the amine nitrogen atom is a member of a saturated 5- to 8-membered cycle. Examples of these are azabicyclo compounds. Also suitable are saturated, 5-, 6-, 7- or ⁇ -membered nitrogen heterocycles which carry on the at least one nitrogen atom a Ci-C4 alkyl group such as N-alkyl pyrrolidines, N-alkylpiperidines or N-alkylmorpholines and the like.
  • the base is preferably used in step i) of the process according to the invention, based on one molar equivalent of the malonic ester of the formula (II), in an amount of 0.1 to 20 molar equivalents. Preference is given to using from 0.75 to 1.5 molar equivalents of the base, based on one molar equivalent of the malonic ester of the formula (II).
  • the base based on the malonic acid ester of the formula (II)
  • step (i) the base used in step (i) is simultaneously used as solvent.
  • the reaction can be carried out after work-up of the fused dihydroxypyrimidine of the formula (I) or immediately after the reaction in step (i).
  • the inventive method is particularly suitable for the execution in the form of a "one-pot process", d. H. the compound of the formula (I) obtained in step (i), in which X is OH, is used directly in step (ii) without further work-up.
  • the reaction mixture from step (i) is used in step (ii) of the process.
  • the reaction mixture from step (i) contains the dihydroxy-substituted compound of the formula (I) in the form of the free compounds and / or the corresponding salts.
  • Halogenating agents in the context of the present invention are compounds which, under the given reaction conditions, provide a halogen atom, especially chlorine or bromine.
  • Suitable halogenating agents are, for example, POCb, PCIs, POBr3 or PBr 5 , where the reaction with POCb or PCI5 leads to fused pyrimidines of the formula (I) in which X is chlorine, and the reaction with POBr 3 or PBr 5 to fused pyrimidines of the formula ( I), wherein X stands for bromine.
  • POCl 3 as halogenating agent.
  • Step (ii) of the process according to the invention is preferably carried out at a pressure greater than atmospheric pressure.
  • the pressure is preferably in the range between 1 and 15 bar and more preferably in the range of 2 to 6 bar.
  • the halogenation in step (ii) is carried out in the presence of an excess of halogenating agent, especially POCb, based on the compound of formula (I) obtained in step (i) and / or the corresponding salt ,
  • an excess of halogenating agent, especially POCb based on the compound of formula (I) obtained in step (i) and / or the corresponding salt
  • the halogenating agent, especially POCb based on the compound of the formula (I) obtained in step (i) and / or the corresponding salt in a molar ratio in the range from 10: 1 to 20: 1 and very particularly preferably from 13 : 1 to 17: 1 used.
  • the halogenating agent especially POCb
  • step (ii) the compound of general formula (I) obtained in step (i) and / or the corresponding salt are added under reaction conditions.
  • the unreacted in step (ii) halogenating agent, especially POCb advantageously removed by distillation.
  • the distillative removal of the halogenating agent, especially POCl takes place at a temperature of maximum period of 60 0 C. In order to ensure a substantially complete distillative removal of the halogenating agent, especially POCl at this temperature, this is done preferably at a pressure in the range of 10 to 400 mbar, and more preferably at a pressure of 40 to 100 mbar.
  • Another object of the present invention relates to a method according to the invention, wherein at least one of the steps (i) or (ii) is operated continuously. With particular preference, at least step (ii) of the process according to the invention is operated continuously.
  • the term "continuous process” refers to a process in which at least one of the compounds involved in the reaction is continuously fed to the reaction and at least one of the intermediates or products of the reaction is withdrawn continuously in the form of a discharge from a reaction mixture.
  • the malonic ester of formula (II) and / or the compound of formula (III) can be continuously fed to the reaction and the compound of formula (I) wherein X is OH, the Be taken reaction mixture.
  • the reaction pressure can be reduced continuously or reduced constantly in the continuous process step.
  • step (ii) of the process according to the invention the compound of the formula (I) in which X is continuously fed to OH, especially as a discharge from a continuously carried out process step (i), and / or the halogenating agent. Both are preferably fed so that the halogenating agent is present in the reaction mixture in any significant amount at any time during the continuous process.
  • the compound of the formula (I) wherein X is Cl or Br is taken out in the form of a reaction mixture and subjected to separation. In the separation of reaction mixtures resulting starting compounds and intermediates can be advantageously recycled to the respective process steps.
  • Suitable reactors for the continuous reaction are known in the art and z. As described in Ullmann's Encyclopedia of Industrial Chemistry, Vol. 1, 3rd ed., 1951, p 743 ff.
  • the reaction contained 2.2% of unreacted diethyl 2- (2,4,6-trifluorophenyl) malonate and about 2% of ethanol.
  • reaction mixture After reaching an internal temperature of 150 0 C, the reaction mixture is stirred for 7 h at 150 0 C internal temperature and the following pressure: first 1 h at 800 mbar, then 1 h at 650 mbar, 1 h at 500 mbar, 1 h at 400 mbar, 1 h at 300 mbar and finally 2 h 150 mbar.
  • the ethanol liberated during the reaction is almost completely distilled off.
  • Step (ii) (at atmospheric pressure): The reaction mixture obtained in the form of a viscous oil is converted at 150 0 C in a heated dropping funnel over a period of 17 minutes with stirring to POCb (1897 g, 12.38 mol) at a temperature from 100 0 C to 107 0 C added dropwise. After completion of the addition, the reaction mixture is stirred for a further 10 hours at a temperature of 107 to 115 0 C under reflux. Excess POCb (1575.3 g) is removed by distillation at a temperature of 60 to 105 0 C under reduced pressure (200 mbar). After completion of the distillation, the distillation residue is treated with toluene (420 ml) and cooled to 40 0 C.
  • the resulting solution is then added at 20 to 26 0 C with stirring to a mixture of toluene (420 ml) and water (1048 ml). After heating to 50 0 C and carried out phase separation, a portion of the organic phase (5 - 15%) at a Distilled off pressure of 200 mbar. There were obtained 1006 g of a toluene solution containing 20.9% of the desired compound by quantitative HPLC analysis. The yield for the chlorination step was 85.2%. This corresponds to a yield of 82.4% over both synthesis stages.
  • Step (ii) under elevated pressure:
  • the reaction mixture thus obtained is as a melt at a temperature of 150 0 C via a trace-heated line from the first stirred vessel to POCb (4875.9 g, 31, 49 mol), the other in a Container (HC pressure stirred vessel) at 25 0 C was submitted, given.
  • the pressure vessel is closed and heated to 140 0 C. This creates a pressure of about 2.4 bar.
  • the reaction is complete. During this period, the pressure rises to about 2.6 bar.
  • the contents of the pressure vessel is cooled to 25 0 C, the pressure drops to about 0.15 bar. Then slowly relax.
  • the excess POCl is at reduced pressure (100 mbar) and a temperature of up to 60 0 C removed by distillation. Subsequently, the pressure at 60 0 C gradually reduced to 40 mbar. A total of 4005 g POCb distillate incurred, which can be used in the next attempt instead of fresh POCb.
  • the distillation residue is dissolved by adding toluene (955.7 g). There are about 2620 g of solution. In a further stirred tank, water (2747.8 g) and toluene (960.5 g) are introduced. Subsequently, the toluene solution of the distillation residue (2620 g) within 2 to 3 h at a temperature of 50 0 C is added.
  • Step (i) (not according to the invention): Diethyl 2- (2,4,6-trifluorophenyl) malonate (96%, 226.7 g, 0.75 mol), 3-amino-1H-1, 2,4- Triazole (amitrole, 96% pure, 65.7 g, 0.75 mol) and tributylamine (139.5 g, 0.75 mol) are initially charged at room temperature in an apparatus with distillation bridge, heated with stirring to 150 0 C (Stickstoffeinper - Lung) and 6 hours at 150 0 C. This incurred about 61 g of distillate.
  • Step (ii): The resulting reaction mixture (viscous oil) is cooled to 120 0 C and then at a temperature of 120 to 130 0 C phosphoryl chloride (689.9g, 4.5 mol) over about 1 h was added. After the addition is stirred at 125 0 C (reflux) for 7 hours. At 130 to 135 0 C phosphoryl chloride is distilled off. After completion of the distillation, the distillation residue (crude Dichlortriazolo- pyrimidine) is cooled to 100 0 C and added dropwise at 40 to 50 0 C to a mixture of 838 ml ToIu- ol and 1048 ml of water. After 30 minutes of stirring at 50 0 C, the phase separation is performed. The organic phase contains 19.4% of the desired dichlorotriazolopyrimidine ( 179.6 g). Yield over both synthesis steps: 74.9%. Yield for chlorination step: 78.9%.

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  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP08701400A 2007-01-11 2008-01-10 Verfahren zur herstellung arylsubstituierter anellierter pyrimidine Withdrawn EP2111404A1 (de)

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EP08701400A EP2111404A1 (de) 2007-01-11 2008-01-10 Verfahren zur herstellung arylsubstituierter anellierter pyrimidine
PCT/EP2008/050254 WO2008084082A1 (de) 2007-01-11 2008-01-10 Verfahren zur herstellung arylsubstituierter anellierter pyrimidine

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