WO2014056900A1 - Procédé de production d'azulène et de dérivés d'azulène - Google Patents

Procédé de production d'azulène et de dérivés d'azulène Download PDF

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WO2014056900A1
WO2014056900A1 PCT/EP2013/070927 EP2013070927W WO2014056900A1 WO 2014056900 A1 WO2014056900 A1 WO 2014056900A1 EP 2013070927 W EP2013070927 W EP 2013070927W WO 2014056900 A1 WO2014056900 A1 WO 2014056900A1
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radical
atom
replaced
formula
divalent
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PCT/EP2013/070927
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Heinz Langhals
Moritz EBERSPÄCHER
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Ludwig-Maximilians-Universität München
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Priority claimed from DE201210019843 external-priority patent/DE102012019843A1/de
Priority claimed from DE102013010911.6A external-priority patent/DE102013010911A1/de
Application filed by Ludwig-Maximilians-Universität München filed Critical Ludwig-Maximilians-Universität München
Priority to DE112013004946.5T priority Critical patent/DE112013004946A5/de
Publication of WO2014056900A1 publication Critical patent/WO2014056900A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
    • C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
    • C07C2602/30—Azulenes; Hydrogenated azulenes

Definitions

  • Azulen and azuiene derivatives are appreciated for their anti-inflammatory effects (see (a) A. E, Sherndal, J. Am. Chem Soc 1915, 37, 1537-1544; (b) L. Ruzicka, EA Rudolph, Helv. Chim Acta 1926, 9, 18-140. (C) A. Pfau, P. Plattner, Helv. Chim. Acta 1936, 19. 858-879; (d) P. Plattner, Helv. Chim. Acta 1941, 24; 283-294). These compounds can be obtained, for example, as active ingredients from chamomile. In addition to azulene itself, guayazulas and chamazulas are mentioned here, which are formally composed of three isoprene units.
  • the next step in the Ziegler-Hafner synthesis is a condensation with a cyclopentadienyl anion and finally a ring closure with elimination of dimethylamine, which is formulated as an electrocyclic ring closure.
  • the ring opening is made with Dimethyiamin as an auxiliary base, which is consuming to handle as a gaseous amine under normal conditions.
  • Dimethyiamin As an auxiliary base, which is consuming to handle as a gaseous amine under normal conditions.
  • it is used as a solution in pyridine.
  • the volatility of dimethylamine is a problem in the synthesis of azulene and requires a relatively complicated design.
  • Specific techniques to provide a solution of dimethylamine in pyridine are described. Hafner and Meinhardt have therefore already searched for less volatile substitutes (K. Hafner, K.-P. Meinhardt, Org. Synth. 1984, 62, 134-137).
  • no reaction could be achieved with N-methylaniline, while diethylamine led to problems in the reaction.
  • the purification of the azulene is carried out by Hafner by means of steam distillation and subsequent extraction (K Hafner, Liebigs Ann. Chem. 1957, 606, 79-89).
  • Hafner Liebigs Ann. Chem. 1957, 606, 79-89.
  • relatively large volumes of water condensate must be collected, which is also due to the low solubility of azulene in water.
  • the synthetic extraction of azulene is thus complex, which is reflected also in the relatively high price of the substance. Also, the number of scientific publications dealing with this substance are low, which can also be attributed to the difficult accessibility. Straightforward access would therefore bring significant progress.
  • the object of the present invention was therefore to provide a simpler, yet efficient process for the preparation of azulene and alzulene derivatives.
  • the present invention therefore provides a process for the synthesis of azulene or an azulene derivative of the general formula (II):
  • radicals R 1 to R 8 may be identical or different and are independently selected from a hydrogen atom, a halogen atom, a cyano group, a linear alkyl radical, a radical - (CH 2 ) "- phenyl. a radical - (CH 2 ) n -pyridyl, a radical - (CH 2 ) n -thiophene, where n is an integer from 0 to 6, a naphthalene radical in which one or two CH groups may be replaced by nitrogen atoms, or an anthracene radical in which one or two CH groups may be replaced by nitrogen atoms,
  • linear alkyl radical is an alkyl radical having at least one and at most 37 C atoms, in which one to 10 CH 2 units can be replaced independently of one another by a carbonyl group in each case.
  • an oxygen atom, a sulfur atom, a selenium atom, a tellurium atom, an cis- or trans-CH CH group in which a CH unit may also be replaced by a nitrogen atom, an acetylenic C 1 -C 4 group, a divalent phenyl radical (for example, a 1, 2, 1, 3 or 1, 4-phenyl).
  • a divalent pyridine residue, a divalent thiophene residue. a divalent naphthalene radical in which one or two CH groups may be replaced by nitrogen atoms, or a divalent anthracene radical in which one or two CH groups may be replaced by nitrogen atoms,
  • up to 12 individual hydrogen atoms of the CH groups in an alkyl radical may each be independently replaced on the same carbon atom by a halogen atom, a cyano group, or a linear alkyl chain having up to 18 carbon atoms, in which one to 6 CH 2 units can be replaced independently of each other by a carbonyl group.
  • R 4 to R 8 are as defined above for formula (II) to form a pyridinium cation; b) reaction of the pyridinium cation with a secondary amine; c) reacting the reaction product of b) with a cyclopentadienyl anion or an anion of a cyclopentadienyl derivative of the formula (IV)
  • radicals R 1 to R 3 are as defined above for formula (II); characterized in that the secondary amine used in step b) is a cyclic amine with the group -NH- as constituent of a heterocyclic ring.
  • the process according to the invention is suitable for the synthesis of azulene or azulene derivatives of the formula (II)
  • the radicals R 1 to R 8 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, a cyano group. a linear alkyl radical. a radical - (CH 2 ) n -phenyl, a radical - (CH) n -pyridyl, a radical - (CH 2 ) n -thiophene, where n is an integer from 0 to 6, a naphthalene radical in which one or two CH groups may be replaced by nitrogen atoms or an anthracene radical in which one or two CH groups may be replaced by nitrogen atoms,
  • linear alkyl radical is an alkyl radical having at least one and at most 37 C atoms.
  • a divalent phenyl radical eg a 1, 2 » , 1 .3 or 1, 4-phenyl radical
  • a divalent pyridine radical eg a 2.3-, 2,4-, 2.5-, 2,6-, 3,4- or 3,5-pyridine radical
  • a divalent thiophene radical eg a 2,3-, 2,4-, 2,5- or 3,4-thiophene radical
  • a divalent naphthalene radical eg a 1, 2, 1, 3 , 1, 4, 1, 5, 1.6, 1, 7-, 1, 8, 2,3, 2,6 or 2,7-naphthalene radical.
  • one or two CH groups may be replaced by nitrogen atoms, or a divalent one Anthracene residue (eg a 1, 2, 1, 3, 1, 4, 1, 5, 1, 6, 1, 7, 1, 8, 1, 9, 1, 10, 2 , 3, 2, 6, 2, 7, 2, 9, 2, 10 or 9, 10 anthracene radical) in which one or two CH groups can be replaced by nitrogen atoms,
  • Anthracene residue eg a 1, 2, 1, 3, 1, 4, 1, 5, 1, 6, 1, 7, 1, 8, 1, 9, 1, 10, 2 , 3, 2, 6, 2, 7, 2, 9, 2, 10 or 9, 10 anthracene radical
  • a divalent pyridine moiety eg, a 2,3, 2,4, 2,5, 2,6, 3,4 or 3,5 pyridine moiety
  • a divalent thiophene moiety eg, a 2,3, 2 , 4, 2,5 or 3,4-thiophene radical
  • a divalent naphthalene radical eg a 1, 2, 1, 3, 1, 4, 1, 5, 1, 6, 1, 7 -
  • 1, 8, 2,3, 2,6 or 2,7-naphthalene radical in which one or two CH groups can be replaced by nitrogen atoms, or a divalent anthracene radical (for example a 1, 2,
  • a 2,3-, 2,4-, 2,5- or 3,4-thiophene radical a divalent naphthalene radical (eg a 1 .2, 1, 3, 1 .4, 1, 5, 1 , 6-, 1-, 7-, 1-, 8-, 2,3-, 2,6- or 2,7-naphthalene radical) in which one or two CH groups may be replaced by nitrogen atoms, or a divalent anthracene radical (US Pat. eg a 1, 2, 1, 3, 1, 4, 1, 5, 1, 6, 1, 7, 1, 8,
  • n is preferably an integer from 0 to 2, in particular 0 or 1.
  • Halogen unless otherwise defined in a specific context, is F, Cl, Br and I, especially F, Cl and Br.
  • a ring which is optionally formed by two radicals R 1 to R 3 or R 4 to R 8 , is fused with the Azuien skeleton of the formula (II). It may be aromatic but may also have one or more CC double bonds which are not conjugated to the aromatic system of the azulene backbone, or may have no further double bonds in addition to those contained in the azuiene backbone.
  • the radicals R 1 to R 8 are the same or different and are independently selected from a hydrogen atom, a halogen atom, a cyano group and a linear alkyl radical which may be substituted as defined above and in which one or more CH 2 groups may be replaced, and where appropriate, two linear alkyl radicals as defined above, which are located at different positions R 1 to R "or R 4 to R 8 , may be linked together to form a ring.
  • R 1 to R 8 are the same or different and are independently selected from a hydrogen atom and a linear alkyl group, wherein the linear alkyl group is as defined above.
  • R 1 to R 8 in formula (II) are independently selected from a hydrogen atom, Ci-C 6 alkyl, or (Ci-C t -, alkyl) -0- in which context "alkyl” stands for a linear or branched, unsubstituted alkyl unit, without the option of replacing a CH or CH 2 unit contained therein preferred are compounds of formula (II) in which the radicals R 1 to R 8 are independently selected from a hydrogen atom and C, -C c , alkyl, wherein a maximum of three of the radicals R 1 to R 8 may be alkyl, most preferably A compound of the formula (II) is azulene, ie the compound of the formula (I):
  • the synthesis process according to the invention starts from pyridine or a pyridine derivative of the formula (III) as starting material:
  • radicals R 4 to R 8 are as defined above for formula (II), including the preferred meanings mentioned.
  • Particular preference is given to using pyridine as the compound of the formula (III), ie R 4 to R 8 are hydrogen atoms. If the compound of the formula (III), such as pyridine, is liquid, it can advantageously be used simultaneously as the reaction solvent, at least for the abovementioned step a).
  • step a) a pyridinium cation is formed by quaternizing the nitrogen atom contained in the ring of the compound of formula (III).
  • the compound of formula (III) is reacted with a reactant such that the nitrogen atom in the pyridine ring of the compound of formula (III) forms a covalent bond with a substituent and a positive formal charge is present on the nitrogen atom.
  • the pyridinium cation is usually in the form of a salt with a suitable counterion.
  • the counterion (anion) for the positive charge may serve, for example, a leaving group, which is split off from said reactant, for example, a halide such as Cl "or Br ⁇ .
  • the quaternization can also be carried out with the aid of an anionic substituent, such that an inner salt is formed together with the pyridinium cation.
  • Suitable reactants and reaction conditions for formation of pyridinium cations are known to those skilled
  • quaternization can be achieved by N-alkylation or N-arylation of the nitrogen atom of the compound of formula (III), or by addition of a cyano group to the nitrogen atom.
  • Methods and reactants for N-alkylation are described, for example, by JR Harjani et al., Green Chem., 2009, 1 1, 83-90
  • the compound of the formula (III) is reacted with a suitable aryl compound, in particular a phenyl compound as a reactant, which carries on the aromatic ring a substituent which is a leaving group in one nucleophilic substitution reaction on the aromatic ring, for example, halo tome, nitro groups, in particular CI.
  • the aromatic ring may contain other known activating groups which facilitate nucleophilic substitution.
  • the quaternization of the nitrogen atom of the compound of formula (III) takes place with an electron-withdrawing substituent which activates the pyridine ring for a nucleophilic ring-opening reaction.
  • an electron-withdrawing substituent which activates the pyridine ring for a nucleophilic ring-opening reaction.
  • Such substituents and suitable reaction conditions of the quaternization reaction are described in detail, for example, in J.Becher, SYNTHESIS, 1980, 589-612 and the literature cited therein.
  • Examples of known electron-withdrawing substituents. which may be linked to the nitrogen atom of the compound of formula (III) to form a pyridinium cation include -SO 3 , -CN. and a 2,4-dinitrophenyl group. Particularly preferred are -CN, or the 2,4-dinitrophenyl group.
  • the quaternization with introduction of the cyano group advantageously takes place by reaction of the compound of the formula (III) with cyanogen bromide (compare W. König, J. Prakt. Chem. 1904, 69, 105-137).
  • the quaternization with introduction of a 2,4-dinitrophenyl group is preferably carried out by reacting the compound of the formula (III) with 1-chloro-2,4-dinitrobenzene.
  • K. Ziegler. K. Hafner Angew Chem 1955 67, 301 or K. Hafner, K.-P. Meinhardt, Org, Synth. 1984 62, 134-137.
  • N- (2,4-dinitrophenyl) pyridinium chloride forms as an intermediate.
  • the reaction of step a) is preferably carried out at elevated temperature, for example in the range from 50 to 100.degree. C., in particular from 70 to 90.degree.
  • pyridine or a pyridine derivative of the formula (III) which is liquid under the reaction conditions is used as starting substance, this starting substance can also be used as solvent for the reaction. In this case, there will usually be an excess of the pyridine or the pyridine derivative of the formula (III) towards the reactant for quaternization.
  • the pyridine or pyridine derivative of the formula (III) can also be reacted in a solvent with the reactant for quaternization, which itself is not involved in the reaction.
  • the pyridine or pyridine derivative of the formula (III) is preferably reacted with the reactant for quaternization in a molar ratio of 1: 1 to 2: 1.
  • step a) pyridine is used both as starting substance and as reaction solvent.
  • step a) of the process according to the invention can be isolated and optionally purified, but it can also be subjected directly to the following step b).
  • step b) the pyridinium cation formed in step a), e.g. N- (2,4-dinitrophenyl) pyridinium chloride reacted with a cyclic secondary amine containing the group -NH- as part of a heterocyclic ring.
  • the cyclic secondary amine is preferably liquid at standard pressure (100 kPa) above a temperature of -5 ° C and has at this pressure a boiling point of 40 to 160 ° C, in particular from 50 to 130 ° C.
  • the cyclic amine preferably has a ring having from 3 to 8, particularly preferably 4 to 6 and particularly preferably 5 or 6 ring atoms.
  • the heterocyclic ring of the cyclic secondary amine preferably contains at most one further heteroatom. If another heteroatom is present, it is preferably a further nitrogen atom. Particularly preferred are cyclic secondary amines which contain, in addition to the group -NH- as a constituent of a heterocyclic ring no further heteroatom among the ring atoms.
  • the heterocyclic ring of the cyclic secondary amine may be a saturated ring, or may contain one or two double bonds. Preferred is a saturated ring.
  • the heterocyclic ring of the cyclic secondary amine may carry one or more substituents, e.g. B. can be selected from alkyl, alkenyl, alkaryl, aryl, alkoxy or halogen.
  • substituents e.g. B. can be selected from alkyl, alkenyl, alkaryl, aryl, alkoxy or halogen.
  • the heterocyclic ring of the cyclic secondary amine does not bear any substituents on the ring atoms adjacent to the group -NH-.
  • Particularly preferred are cyclic secondary amines which do not carry substituents on the heterocyclic ring.
  • Cyclic secondary amines selected from piperidine, pyrrolidine, azetidine, aziridine and mixtures thereof have proven particularly suitable for the process according to the invention. Of these, in turn, piperidine and pyrrolidine are preferred, and pyrrolidine is most preferred.
  • step b In the context of the implementation of step b), it is assumed that a nucleophilic ring opening of the pyridine ring occurs. However, as a rule, the intermediate formed is not necessarily isolated during the synthesis of the compound of formula (I), before the subsequent step c) is carried out.
  • the amine may e.g. as a pure substance or in the form of a solution of a solution or a suspension of the pyridinium salt are added dropwise.
  • the reaction takes place first at a temperature of -5 to 10 ° C, wherein after the addition, the temperature can be increased to room temperature.
  • the reaction of the pyridinium cation with a secondary amine is preferably carried out in a solvent.
  • the solvent may be used here, in which the reaction of step a) has already been carried out.
  • Particularly preferred as solvent is thus pyridine.
  • At least two moles of the secondary amine per mole of the pyridinium cation are preferably used in the reaction in step b).
  • the amount of secondary amine is particularly preferably in the range from 2 to 4 moles per mole of the pyridinium cation, in particular in the range of 2 2 to 3 moles.
  • the amount of secondary amine can also be calculated in relation to the amount of quaternization reactant.
  • the reaction in step b) preferably at least two moles of the secondary amine per mole of quaternization reactant can be used, and particularly preferred are amounts of the secondary amine in the range of from 2 to 4 moles per mole of quaternization reactant, especially Range of 2.2 to 3 moles.
  • step c) the reaction product from step b) is reacted with a cyclopentadienyl anion or an anion of a cyclopentadienyl derivative of the formula (IV)
  • R 1 to R 5 are as defined above for formula (II), including the preferred meanings mentioned.
  • the cyclopentadienyl anion is particularly preferably used as the compound of the formula (IV), ie R 1 to R 3 are hydrogen atoms.
  • cyclopentadienyl anion or the anion of a cyclopentadienyl derivative of the formula (IV) is preferably prepared in situ by reacting in step c) the reaction product from step b) with cyclopentadiene or a cyclopentadiene derivative of the formula (IVa)
  • Suitable bases are, for example, alkoxides, in particular alkali metal salts of alcohols. Typically, these are aliphatic alcohols, preferably methanol or ethanol. For example, sodium methoxide can be used as the base.
  • the base can be obtained, for example, so that the alkali metal is dissolved in an excess of the alcohol. In this way, an alcoholic solution of the alkali metal alcoholate, which can be reacted with the cyclopentadiene or cyclopentadiene derivative of the formula (IVa), is obtained.
  • the cyclopentadiene or cyclopentadiene derivative of the formula (IVa) may first be added to the reaction product from step b).
  • the alcoholate is added dropwise to the mixture as a solution.
  • the intermediate formed in step b) of the process according to the invention can be isolated and optionally purified, but it can also be subjected directly to the following step c).
  • the reaction of step c) can be carried out, for example, at temperatures between 0 and 50 ° C, room temperature (20 ° C) is preferred.
  • the duration of the implementation can be several hours, z. B. 2 to 24 hours.
  • the reaction is preferably carried out in a solvent.
  • the solvent may be used here in which the reaction of step a) and / or b) has already been carried out. Particularly preferred as solvent is thus pyridine.
  • step c) at least one mole of the cyclopentadiene or of the cyclopentadiene derivative of the formula (IVa) is used per mole of the reaction product from step b). More preferably, the amount of cyclopentadiene or cyclopentadiene derivative of formula (IVa) is in the range of from 1.05 to 2 moles per mole of the per mole of reaction product of step b), especially in the range of from 1.05 to 1.5 moles the reaction is carried out without isolating the intermediates from step a) and b), the amount of cyclopentadiene or cyclopentadiene derivative of formula (IVa) can also be calculated in relation to the amount of quaternization reactant.
  • step c) preferably at least one mole of the cyclopentadiene or of the cyclopentadiene derivative of the formula (IVa) can be used per mole of the quaternization reactant, and amounts of the secondary amine in the range of 1, 05 to 2 moles per mole of quaternizing reactant, in particular in the range of 1, 05 to 1, 5 mol.
  • the process according to the invention also comprises a step d) of heating a product formed in step c) by attaching a cyclopentadienyl anion or an anion of a cyclopentadienyl derivative of the formula (IV) to the reaction product from b) becomes.
  • the reaction of the reaction product from step b) with a cyclopentadienyl anion or an anion of a cyclopentadienyl derivative of the formula (IV) in step c) first gives an intermediate in which there is a covalent bond between the reaction partners of step c), and from forms the compound of formula (II) with ring closure.
  • step d it is generally desired to accelerate the ring closure by supplying energy, in particular heat energy according to step d).
  • step d preferably a solution or suspension of the product from step c) is heated.
  • the reaction mixture from step c) can be heated immediately.
  • an alcoholic solution of an alcoholate may be used which may be used as an alcoholic solution.
  • step d) is heated to reflux at the boiling temperature of the solution or suspension of the product of step c).
  • the temperature to which the product from step c) is heated is 70 to 140 ° C., preferably 90 to 120 ° C., in particular 90 to 15 ° C.
  • the heating in step d) may be carried out for several hours or several days as required, e.g. 2 hours to 14 days, especially 1 day to 8 days.
  • the isolation and optionally the purification of the azulene or of the azulene derivative of the formula (II) which is prepared by the process according to the invention can be carried out by known techniques. It has proven to be advantageous to isolate the azulene or azulene derivative of the formula (II) with the aid of steam distillation from the reaction mixture obtained from step c), if appropriate in combination with the subsequent step d). From the obtained steam distillate, the compound of formula (II) can be recovered by extraction. However, in a simple steam distillation, large volumes of water condensate must be collected and then extracted.
  • the isolation of the compound of formula (II) can be achieved by using a steam distillation with simultaneous extraction of the product with an organic solvent (eg Hünig et al., "Working Methods in Organic Chemistry", Lehmanns, Berlin 2006, Chapter 4.4)
  • an organic solvent eg Hünig et al., "Working Methods in Organic Chemistry", Lehmanns, Berlin 2006, Chapter 4.4
  • the condensate from the steam distillation is continuously brought into contact with an organic solvent, and can then be recycled to the extraction.
  • the steam distillation can be carried out continuously until complete isolation of the product formed, while the extraction can also run continuously in parallel ,
  • an alkane e.g. Hexane.
  • Isohexane is e.g. because of the lower neurotoxicity to n-hexane as also a viable alternative to prefer
  • Any residues of pyridine or pyridine derivatives remaining in the organic solvent may be removed by shaking with aqueous mineral acid, e.g. aqueous HCl, can be easily removed.
  • aqueous mineral acid e.g. aqueous HCl
  • the extraction in particular combined steam distillation and extraction may, if necessary, follow further purification steps. Further purification can be carried out, for example, by chromatography. This can be carried out for a compound of the formula (II), for example with isohexane as the mobile phase.
  • alumina basic II
  • a high-purity product of the formula (II), in particular azulene. may be supported by vacuum sublimation. This can be carried out, for example, at 200 mbar and 75 ° C.
  • the synthesis of compounds of the formula (II) is considerably simplified by the use according to the invention of secondary cyclic amines. Working up by means of a steam distillation combined with a continuous extraction, preferably with isohexane, leads to a further advance. For example, the handling of larger laboratory approaches is considerably improved and uncritical scaling up in the art is permitted.
  • IR spectra were recorded on a Perkin Elmer 1420 Ratio Recording Infrared Spectrometer, FT 1000.
  • UV-Ais spectra were measured using a Varian Gary 5000 and Bruins Omega 20.
  • a Varian Eclispe was used to measure the fluorescence spectra.
  • Mass spectrometry was performed on a Finnigan Model MAT 95 instrument.
  • Fluorescence quantum yields were determined as described by H. Langhals, J. Karolin and L. B.-A. Johansson in J. Chem. Soc. Faraday Trans. 1998, 94. 2919-2922.
  • phase divider with reflux condenser was attached with a collecting flask with isohexane (300 mL) and the reaction vessel filled with distilled water (300 mL). Half of the phase splitter was filled with water and isohexane. The batch was heated to reflux (bath 125 ° C) as well as the isohexane, so that a steam distillation was combined with a continuous extraction with isohexane. Azulene was extracted until the overflowing isohexane was colorless.
  • the deep blue isohexane phase was washed with 2 M aqueous HCl (3 ⁇ 100 ml), with distilled water, dried over sodium sulfate, concentrated, purified by chromatography (Al 2 O 3 basic act. II, isohexane, first, intense blue band) , filtered through a D5 glass frit and evaporated to dryness.
  • IR (ATR): v 3075.8 (vw), 2958.5 (vw), 2923.8 (w), 2853.8 (vw), 1816.3 (w), 1641, 8 (br), 1569 , 9 (w), 1530.5 (w), 1475.8 (m), 1452.3 (w), 1437.8 (w), 1389.2 (w), 1296.0 (w), 1260, 8 (vw), 1204.3 (m), 1 1 51 .9 (vw), 1051, 7 (w), 1012.2 (w), 984.2 (w), 965.0 (m), 952.1 (m), 897.3 (w), 823.6 (w), 792.2 (w), 755.0 (vs), 725.3 (s), 674.3 cm 1 (m);
  • Example 2 (Piperidine as amine) Under nitrogen, 1-chloro-2,4-dinitrobenzene (20.3 g, 100 mmol) was heated with dry pyridine (120 mL) to 90 ° C. with mechanical stirring for 4 h (formation of a voluminous precipitate, first colorless, later yellowish and finally brown), cooled to 0 ° C., slowly added dropwise with a solution of piperidine (21, 8 mL, 220 mmol) in 30 mL dry pyridine (clarification and intense red coloration), stirred at room temperature for 16 h, with freshly distilled cyclopentadiene (8.68 mL, 105 mmol) and then with a Solution of sodium (2.30 g, 100 mmol) in methanol (40.0 mL) slowly added dropwise, stirred for 16 h at room temperature, over a Vigreux column (30 cm, bath to 130 ° C) up to a head temperature of 95 ° C concentrated, cooled to room temperature,
  • phase divider with reflux condenser was attached to a collection flask with isohexane (300 mL) and the reaction vessel was filled with distilled water (300 mL). Half of the phase splitter was filled with water and isohexane. The batch was heated to reflux (bath 125 ° C) as well as the isohexane, so that a steam distillation was combined with a continuous extraction with isohexane. Azulene was extracted until the overflowing isohexane was colorless.
  • the deep blue isohexane phase was washed with 2 M aqueous HCl (3 ⁇ 100 ml), with distilled water, dried over sodium sulfate, concentrated, purified by chromatography (Al 2 O 3 basic act. II, isohexane, first, intense blue band) filtered through a D5 glass filter and evaporated to dryness.
  • phase divider with reflux condenser was attached to a collection flask with isohexane (300 mL) and the reaction vessel was filled with distilled water (300 mL). Half of the phase splitter was filled with water and isohexane. The batch was heated to reflux (bath 125 ° C) as well as the isohexane, so that a steam distillation with a continuous extraction was associated with isohexane. Azulene was extracted until the overflowing isohexane was colorless.
  • the deep blue isohexane phase was washed with 2 M aqueous HCl (3 x 100 ml_), washed with distilled water, dried over sodium sulfate, concentrated, purified by chromatography (Al 2 0 3 basic act. II, isohexane, first, intense blue band) , filtered through a D5 glass frit and evaporated to dryness.

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Abstract

L'invention concerne un procédé de synthèse d'azulène ou d'un dérivé d'azulène, comprenant les étapes suivantes: (a) quaternisation de pyridine ou d'un dérivé de pyridine, avec formation d'un cation pyridinium; (b) mise en réaction du cation pyridinium avec une amine secondaire cyclique; et (c) conversion du produit réactionnel obtenu à l'étape (b) avec un anion cyclopentadiényle ou un anion d'un dérivé de cyclopentadiényle.
PCT/EP2013/070927 2012-10-09 2013-10-08 Procédé de production d'azulène et de dérivés d'azulène WO2014056900A1 (fr)

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DE201210019843 DE102012019843A1 (de) 2012-10-09 2012-10-09 Synthese von Azulen und Azulenderivaten und deren Verwendung
DE102013010911.6A DE102013010911A1 (de) 2013-06-28 2013-06-28 Verfahren zur Herstellung von Azulen und Azulenderivaten
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Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
A. E. SHERNDAL, J. AM. CHEM. SOC., vol. 37, 1915, pages 1537 - 1544
A. PFAU; P. PLATTNER, HELV. CHIM. ACTA, vol. 19, 1936, pages 858 - 879
H. LANGHALS; J. KAROLIN; L. B.-A. JOHANSSON, J. CHEM. SOC., FARADAY TRANS., vol. 94, 1998, pages 2919 - 2922
HÜNIG ET AL.: "Arbeitsmethoden in der organischen Chemie", 2006, VERLAG LEHMANNS
J.BECHER, SYNTHESIS, 1980, pages 589 - 612
J.R. HARJANI ET AL., GREEN CHEM., vol. 11, 2009, pages 83 - 90
K. HAFNER, LIEBIGS ANN. CHEM., vol. 606, 1957, pages 79 - 89
K. HAFNER; K.-P. MEINHARDT, ORG. SYNTH, vol. 62, 1984, pages 134 - 137
K. HAFNER; K.-P. MEINHARDT, ORG. SYNTH., vol. 62, 1984, pages 134 - 137
K. ZIEGLER; K. HAFNER, ANGEW. CHEM., vol. 67, 1955
K. ZIEGLER; K. HAFNER, ANGEW. CHEM., vol. 67, 1955, pages 301
KARL ZIEGLER ET.AL.: "Eine rationelle Synthese des Azulens", ANGEW. CHEM., vol. 67, 1955, pages 301, XP002717719 *
KLAUS HAFNER ET.AL.: "Azulene", ORG. SYNTH., vol. 62, 1984, pages 134 - 137, XP002717718 *
L. RUZICKA; E. A. RUDOLPH, HELV. CHIM. ACTA, vol. 9, 1926, pages 118 - 140
P. PLATTNER, HELV. CHIM. ACTA, vol. 24, 1941, pages 283 - 294
T. ZINCKE; W. WÜRKER, LIEBIGS ANN. CHEM., vol. 338, 1904, pages 107 - 141
W. KÖNIG, J. PRAKT. CHEM., vol. 69, 1904, pages 105 - 137
ZERONG WANG: "Ziegler-Hafner Synthesis", COMPREHENSIVE ORGANIC NAME REACTIONS AND REAGENTS, 15 September 2010 (2010-09-15), pages 3139 - 3143, XP002717717 *

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