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WO2020126645A1 - Procédé de préparation d'acide 2-(3, 4-diméthyl-1h-pyrazole-1-yl) succinique et d'acide 2-(4, 5-diméthyl-1h-pyrazole-1-yl) succinique dans un système de solvant à deux phases - Google Patents

Procédé de préparation d'acide 2-(3, 4-diméthyl-1h-pyrazole-1-yl) succinique et d'acide 2-(4, 5-diméthyl-1h-pyrazole-1-yl) succinique dans un système de solvant à deux phases Download PDF

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Publication number
WO2020126645A1
WO2020126645A1 PCT/EP2019/084341 EP2019084341W WO2020126645A1 WO 2020126645 A1 WO2020126645 A1 WO 2020126645A1 EP 2019084341 W EP2019084341 W EP 2019084341W WO 2020126645 A1 WO2020126645 A1 WO 2020126645A1
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Prior art keywords
pyrazole
phase
succinic acid
dimethyl
process according
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Timo Frassetto
Horst Mayer
Dieter BRENDEL
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BASF SE
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • C—CHEMISTRY; METALLURGY
    • C05—FERTILISERS; MANUFACTURE THEREOF
    • C05G—MIXTURES OF FERTILISERS COVERED INDIVIDUALLY BY DIFFERENT SUBCLASSES OF CLASS C05; MIXTURES OF ONE OR MORE FERTILISERS WITH MATERIALS NOT HAVING A SPECIFIC FERTILISING ACTIVITY, e.g. PESTICIDES, SOIL-CONDITIONERS, WETTING AGENTS; FERTILISERS CHARACTERISED BY THEIR FORM
    • C05G3/00—Mixtures of one or more fertilisers with additives not having a specially fertilising activity
    • C05G3/90—Mixtures of one or more fertilisers with additives not having a specially fertilising activity for affecting the nitrification of ammonium compounds or urea in the soil

Definitions

  • the present invention relates to a process for preparing an isomer mixture comprising 2-(3,4- dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof comprising the step of reacting 3,4-dimethylpyrazole with at least one a , b -unsaturated dicarbonyl compound selected from the group consisting of maleic acid, maleic acid anhydride and fumaric acid in a two solvent system comprising water and at least one organic solvent, in such a manner that the two solvent system is a two phase system or be comes a two phase system during the two-phase-formation step where the product can be iso lated from the aqueous phase without solid handling.
  • Nitrogen is an essential element for plant growth and reproduction. About 25% of the plant- available nitrogen in soils (ammonium and nitrate) originates from decomposition processes (mineralization) of organic nitrogen compounds such as humus, plant and animal residues and organic fertilizers. Approximately 5% derive from rainfall. On a global basis, the biggest part (70%), however, are supplied to the plant by inorganic nitrogen fertilizers. Without the use of ni trogen fertilizers, the earth would not be able to support its current population.
  • Soil microorganisms convert organic nitrogen to ammonium (NhV) which is subsequently oxi dized to nitrate (NOg) in a process known as nitrification.
  • NhV ammonium
  • NOg nitrate
  • nitrate is highly mobile in the soil and may be readily lost from soils by leaching to ground water. Nitrogen is further lost by microbiological denitrification to gaseous forms of nitrogen. As a result of the various losses, approximately 50% of the applied nitrogen is lost during the year following fertilizer addition (cf. Nelson and Huber; Nitrification inhibitors for corn production (2001), Na tional Corn Handbook, Iowa State University).
  • Nitrification inhibitors such as pyrazole compounds can be used in order to increase fertiliza tion efficacy and consequently decrease nitrogen levels in the groundwater and surface waters and nitrogen oxide levels in the atmosphere.
  • a problem associated with the use of pyrazole compounds is their volatility, which makes them difficult to store and difficult to further process.
  • WO 96/24566 describes methods of producing non-volatile pyrazole derivatives with hydro philic groups to be used as nitrification inhibitors. It is inter alia described that pyrazole deriva tives can be reacted with maleic acid anhydride for example to obtain 2-(N-3-methyl-pyrazole).
  • WO 2011/032904 and WO 2013/121384 describe 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid as nitrification inhibitor.
  • WO 2015/086823 and WO 2016/207210 inter alia relate to a method of producing an isomer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid by reacting 3,4-dimethylpyra- zole with maleic acid and/or maleic acid anhydride in the absence of organic solvents and organic diluents followed by crystallization of the reaction product in order to obtain a satisfying purity of the desired product.
  • an aqueous solution of the isomer mixture which may, e.g., be used for preparing an agricultural formulation.
  • It is a second object of the present invention to provide a further process for preparing an iso mer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and 2- (4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof, which represents a new synthetic route for obtaining the desired product, but also provides the desired product in a high purity and a high yield.
  • the present invention relates to a process, which is in the following referred to as process A, for preparing an isomer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) suc cinic acid or salts thereof and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof comprising the step of reacting 3,4-dimethylpyrazole with at least one a , b -unsaturated dicar bonyl compound selected from the group consisting of maleic acid, maleic acid anhydride and fumaric acid in a two solvent system or in a two phase system comprising water and at least one organic solvent.
  • process A for preparing an isomer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) suc cinic acid or salts thereof and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof comprising the step of reacting 3,4-dimethylpyrazo
  • the present invention relates to an aqueous solution comprising an isomer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and 2-(4,5-dimethyl- 1 H-pyrazole-1-yl) succinic acid or salts thereof having a pH in the range of from 4 to less than 12, preferably from 4 to less than 11 , more preferably from 4 to less than 10, most preferably from 5 to less than 8.5, particularly from 5 to less than 7.
  • the second object of the invention is achieved by the process B as described hereinafter and in independent claim 12 and claims directly or indirectly depending thereon and independent claim 14.
  • the present invention therefore relates to a process, which is in the follow ing referred to as process B, for preparing an isomer mixture comprising 2-(3,4-dimethyl-1 H-py- razole-1-yl) succinic acid or salts thereof and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof by reacting 3,4-dimethlypyrazole with fumaric acid in the absence of an organic solvent.
  • Fumaric acid was not described as a suitable starting material for the preparation of an isomer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid and 2-(4,5-dimethyl-1 H-pyra- zole-1-yl) succinic acid before.
  • the inventors of the present invention have surprisingly found out that this starting material also provides the desired reaction product in high yields and high purities, and that the reaction may be performed in the absence of an organic solvent.
  • the present invention relates to an aqueous solution obtainable by dissolving the isolated isomers of the reaction product of process B in water and by adjusting the pH to less than 12 using at least one base selected from the group consisting of alkali hydroxides, earth alkali hydroxides and ammonium hydroxide, in particular from the group consisting of NaOH, KOH and NH 4 OH.
  • Independent claim 15 relates to a novel isomer mixture comprising 2-(3,4-dimethyl-1 H-pyra- zole-1-yl) succinic acid in the form of an ammonium salt and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid in the form of an ammonium salt.
  • the present invention relates to an isomer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid diammonium salt and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid diammonium salt.
  • the term“isomer” describes compounds with the same chemical formula and molecular weight, but different chemical structures.
  • two isomers are formed as the reaction product due to a tautomerization reaction of the starting ma terial 3,4-dimethylpyrazole, which takes place at elevated temperatures.
  • the two isomers 2-(3,4-dimethyl-1 H-pyrazole-1- yl) succinic acid or salts thereof and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof are formed, which only differ in terms of the position of the methyl groups at the pyrazole group.
  • the process is for preparing an isomer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and 2-(4,5-dimethyl- 1 H-pyrazole-1-yl) succinic acid or salts thereof.
  • the isomers of the reaction product it is referred to the two isomers ob tained by the process of the present invention, i.e. the isomer 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and the isomer 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof.
  • the reaction product when it is referred to“the reaction product”, it is referred to the isomer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and 2-(4,5- dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof.
  • salts of the isomers of the reaction product include salts that are formed by deprotonating one or both of the acidic groups of the succinic acid moiety.
  • salts of the iso mers of the reaction product include salts wherein the isomers of the reaction product are mono-anions or di-anions, and form a salt with one or two cations including alkali metal cations, earth alkali metal cations or ammonium cations.
  • the salts are formed by reacting the isomers in the form of the acid with a base.
  • Suitable bases according to the invention include alkali hydroxides, earth alkali hydroxides, ammonium hydroxides and gaseous ammonia.
  • the isomers are provided in the form of an alkali, earth alkali or ammonium salt, wherein the isomers of the reaction product may be present as mono- or di-anions, preferably as di-anions.
  • Hydroxides can be preferred as bases, as water is formed as the only byproduct of the salt formation. If ammonia is used as base, no byproduct is formed.
  • the term“two solvent system” describes a more or less homogeneous reac tion environment comprising two solvents, from which one solvent is water and the other solvent is an organic solvent, and which - in case the two solvent system is not a two phase system from the beginning - can be simply turned into a two phase system during the two-phase-for- mation step, for example via addition of water and/or the adjustment of the pH value.
  • the two solvent system can be one single phase, or can be a two phase system, depending on one or more of the following conditions or parameters:
  • the two solvent system is a two phase system or be comes a two phase system during the two-phase-formation step.
  • the term“two phase system” describes a heterogeneous reaction environ ment comprising two immiscible phases.
  • the two different phases are formed by using two immiscible solvents, e.g. water and an organic solvent, which is immiscible with water.
  • the solvent with the lower density will form the upper layer of the two-phase system, and the solvent with the higher density will form the lower layer of the two-phase system.
  • stirring is preferably used in order to increase the interfacial area of the two phases and thus optimize the reaction.
  • Various emulsification techniques have been developed to produce droplets from micrometer to nanometer scale. For details in this regard, reference is made to Keti Piradashvili et al., Chem.
  • the a , b -unsaturated dicarbonyl compound is predominantly present in the water phase and the 3,4-dimethylpyrazole is predominantly present in the organic phase.
  • the addition of a phase transfer catalyst, which is soluble in both phases, may facilitate the transfer of a reactant from one phase to another.
  • a phase transfer catalyst is a catalyst that facilitates the migration of a reactant from one phase into another phase where the reaction occurs.
  • Typical examples for anionic reactants are often quaternary ammonium salts.
  • Commercially important catalysts include benzyltrime- thylammonium chloride, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride.
  • Organic phosphonium salts are also used, e.g., hexadecyltributylphosphonium bromide.
  • organic solvent preferably refers to a solvent that, when mixed with water, is capable of forming a separate phase, i.e. is immiscible with water at least during/after the two-phase-formation step.
  • Preferred organic solvents include alkanes, aromatic solvents, lipophilic alcohols or ketones and ethers.
  • Preferred alkane solvents include aliphatic hydrocar bons such as pentane, hexane, heptane, cyclohexane, petroleum ether, or mixtures thereof.
  • a particularly preferred alkane solvent is heptane.
  • Preferred aromatic solvents are e.g.
  • benzene toluene, xylene (ortho-xylene, meta-xylene or para-xylene), mesitylene, chlorobenzene, 1 ,2-di- chlorobenzene, 1 ,3-dichlorobenzene, 1 ,4-dichlorobenzene, or mixtures thereof.
  • a particularly preferred aromatic solvent is toluene.
  • Preferred lipophilic alcohols are cycloalkanols or alkanols, more preferably cyclohexanol, n-butanol, i-butanol, 2-ethylhexanol or n-octanol.
  • Preferred lipophilic ketones are alkanones, or cycloalkanones, more preferably cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone, cyclooctanone, most preferably cyclohexa none.
  • the organic solvent is cyclohexanone.
  • Preferred ethers are open-chained and cyclic ethers, in particular diethyl ether, methyl-tert-bu- tyl-ether (MTBE), 2-methoxy-2-methylbutane, cyclopentylmethylether, 2-methyltetrahydrofuran, or mixtures thereof.
  • a particularly preferred ether solvent is MTBE.
  • aqueous solution describes a homogenous single-phase mixture in which the solvent is water.
  • reaction steps are performed in reaction vessels customary for such reactions e.g. conventional stirred tank reactors.
  • the reactions may be carried out in a continuous, semi- continuous or batchwise manner.
  • reaction steps are preferably carried out under atmospheric pressure.
  • reaction of 3,4-dimethylpyrazole with at least one a , b -unsaturated dicarbonyl compound may also be carried out under a certain pressure, e.g. if it is intended to perform the reaction at a higher temperature than the boiling points of the solvents.
  • the temperatures and the duration times of the reactions may be varied in broad ranges, which the person skilled in the art knows from analogous reactions.
  • the temperatures often de pend on the reaction temperature of the solvents.
  • the end of the reaction can be monitored by methods known to a person skilled in the art, e.g. thin layer chromatography, HPLC or NMR.
  • reactants can in principle be contacted with one another in any desired sequence.
  • reaction steps may each be performed on a technical scale.
  • the reactants are covered equally well and only minor deviations in terms of the yield are observed.
  • process A of the invention is provided. It is to be understood that the preferred embodiments to be illustrated below of process A of the in vention are preferred alone or in combination with each other.
  • the present invention relates in a first aspect to the process for preparing an isomer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof comprising the step of reacting 3,4-dimethylpyrazole with at least one a , b -unsaturated dicarbonyl compound se lected from the group consisting of maleic acid, maleic acid anhydride and fumaric acid in a two solvent system or a two phase system - preferably in a two solvent system - comprising water and at least one organic solvent.
  • Process A provides the advantage that the isomers of the reaction product are directly ob tained in aqueous solution in high yields and high purity without further, elaborate work-up of the reaction product.
  • the reactants are preferably provided as suspen sion, dispersion or complete solution at the beginning of the reaction.
  • the a , b -un saturated dicarbonyl compound is provided in water
  • the 3,4-dimethylpyrazole is provided in an organic solvent for the process of the present invention.
  • a solu tion of the 3,4-dimethylpyrazole in an organic solvent is added to an aqueous solution or sus pension of the a , b -unsaturated dicarbonyl compound.
  • the order of addition may also be vice versa.
  • the 3,4-dimethylpyrazole may also be provided separately from the organic solvent.
  • Maleic acid anhydride can be dissolved in water thereby at least partly forming maleic acid.
  • Maleic acid itself can also be used and provided as an aqueous solution.
  • Fumaric acid typically forms a suspension in water.
  • the 3,4-dimethylpyrazole is preferably provided as a solution in an organic solvent.
  • Preferred organic solvents include alkanes, aromatic solvents, and ethers as described in further detail below.
  • the at least one organic solvent of the two solvent system or of the two phase system is selected from the group consist ing of an alkane, an aromatic solvent or an ether.
  • the organic solvent is an aromatic solvent, preferably toluene or chlorobenzene.
  • Preferred alkane solvents include aliphatic hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, or mixtures thereof.
  • a particularly preferred alkane solvent is heptane.
  • Preferred aromatic solvents are e.g. benzene, toluene, xylene (ortho-xylene, meta-xy- lene or para-xylene), mesitylene, chlorobenzene, 1 ,2-dichlorobenzene, 1 ,3-dichlorobenzene,
  • ethers are open-chained and cyclic ethers, in particular diethyl ether, methyl-tert-bu- tyl-ether (MTBE), 2-methoxy-2-methylbutane, cyclopentylmethylether, 2-methyltetrahydrofuran, or mixtures thereof.
  • MTBE methyl-tert-bu- tyl-ether
  • 2-methoxy-2-methylbutane 2-methoxy-2-methylbutane
  • cyclopentylmethylether 2-methyltetrahydrofuran
  • a particularly preferred ether solvent is MTBE.
  • the organic solvent is not dichloromethane (DCM).
  • the 3,4-dimethylpyrazole and the at least one a , b - unsaturated dicarbonyl compound are reacted with each other in a molar ratio of from 3: 1 to 1 : 1 , preferably from 1.5:1 to 1 : 1 and more preferably from 1.2: 1 to 1 :1.
  • 3,4-dimethylpyrazole in an excess may shift the chemical equilibrium towards the product side and, thus, lead to an increased yield, while 3,4-dimethylpyrazole may be recycled for the repetition of the reaction in order to use it most effectively. Accordingly, it can be pre ferred according to the invention, to use an excess of the 3,4-dimethylpyrazole.
  • phase transfer catalysts may be added to the reaction mixture.
  • Preferred phase transfer catalysts according to the invention are selected from the group consisting of phospho- nium salts and quaternary ammonium salts.
  • said phase transfer catalysts are ammo nium salts selected from the group of benzyltrimethylammonium chloride, benzyltriethylammo- nium chloride, methyltricaprylammonium chloride and methyltrioctylammonium chloride.
  • phase transfer catalyst it is preferred according to the present invention that no phase transfer catalyst is used, in order to avoid a purification step for removing the phase transfer catalyst from the prod uct mixture.
  • the reaction is preferably performed under stirring to improve the homogeneity of the two sol vent system or to increase the interfacial area of the two phases and thus optimize the reaction.
  • the reaction preferably takes place at a pH of less than 12, more preferably less than 9, most preferably less than 7 due to the acidic groups of the a , b -unsaturated dicarbonyl compound.
  • Suitable temperatures for reacting 3,4-dimethylpyrazole with at least one a , b -unsaturated dicarbonyl compound are in the range of from 20 ° C to 200 ° C, preferably from 50 ° C to 170 ° C, more preferably from 80 ° C to 170 ° C and most preferably from 80 ° C to 100 ° C. If the reaction temperature is above the boiling point of one of the solvents in the reaction mixture, it is to be understood that the reaction will be performed under pressure.
  • the reaction time may vary in broad range, e.g. from 1 hour to 2 days, preferably from 3 to 12 hours.
  • the reaction is performed until complete consumption of the at least one a , b - unsaturated dicarbonyl compound, which may be determined by thin layer chromatography, HPLC or NMR.
  • the starting material 3,4-dimethylpyrazole tautomerizes, and therefore an isomer mixture of the substituted succinic acid is obtained.
  • 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof are obtained in a molar ratio of 5:95 to 95:5, preferably 50:50 to 95:5, more preferably 70:30 to 90:10.
  • the isomeric mixture of 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof is ob tained in a molar ratio of about 80:20.
  • the isomeric ratio can be determined by NMR spectrometry.
  • the purity of the iso mers of the reaction product in the aqueous phase is very high. Accordingly, the isomers of the reaction product can be obtained in a purity of at least 95 %, preferably at least 98 %, more preferably at least 99 % without any further purification step, e.g. crystallization step.
  • the purity of the isomers of the reaction product can also be determined by NMR spectrome try.
  • process A especially in case the two solvent system is one sin gle phase during the reaction of 3,4-dimethylpyrazole with at least one a , b -unsaturated dicar bonyl compound, the process further comprises a two-phase-formation step before the phase separation.
  • the process especially in case the two solvent system is one single phase during the reaction of 3,4-dimethylpyrazole with at least one a , b -unsatura ted dicarbonyl compound, the process further comprises a two-phase-formation step after the step of reacting 3,4-dimethylpyrazole with at least one a , b -unsaturated dicarbonyl compound.
  • the process further comprises a two-phase-formation step after the step of reacting 3,4-dimethylpyrazole with at least one a , b -unsaturated dicarbonyl compound and before the phase separation.
  • the one single phase is turned into two different phases, enabling the phase separation in the next step.
  • the two-phase-formation step occurs through different measures,
  • this two-phase-formaton step occurs through the addition of water in a way that an additional amount of 0.1 g to 7.0 g water, more preferably 0.3 g to 5.0 g, more preferably 0.5 g to 4.0 g water, most preferably 1.0 g to 3.0 g water, particularly 1.2 to 2.0 g water per 1 g of organic solvent which is present in the reaction mixture is added.
  • the process further comprises isolating an aqueous solution comprising the isomers of the reaction product by phase separation.
  • Phase separation is to be understood as the physical separation of the aqueous and the or ganic phase, which is possible due to the different density of the two phases.
  • the phase separation can, e.g., be performed using a separatory funnel.
  • the aqueous phase may be removed from the non-stirred reaction tank, while measuring the con ductivity.
  • a phase separator may be used.
  • a washing step of the aque ous phase with organic solvents can be performed in order to extract residual amounts of 3,4- dimethylpyrazole into the organic phase.
  • the organic phase comprising residual amounts of the 3,4-dimethylpyrazole can then be recycled for the next reaction, while the aqueous phase com prises the desired reaction product.
  • a distillation step may be performed after the phase separation step.
  • the aqueous phase is subjected to a distillation process to remove residual amounts of the organic phase.
  • Distillation is to be understood as a process of separating the aqueous phase from the organic phase by selective evaporation and condensation.
  • the reaction product is obtained in the aqueous phase.
  • a pH value which is not too acidic, i.e. not lower than 4.
  • Suitable bases for adapting the pH include but are not limited to hydroxides of alkali metals such as sodium, potassium, caesium, lithium, hydroxides of alkaline earth metal such as calcium and magnesium, hydroxides of other metals, such as aluminium and zinc, ammonium hydroxide, ammonia and organic amines.
  • phase separation is performed at a tempera ture of from 20 ° C to 140 ° C, preferably from 20 ° C to 100 ° C.
  • the pH of the reaction mixture is adjusted to a value of from 4 to less than 12, more preferably from 4 to less than 11 , most preferably from 4 to less than 10, particularly preferably from 5 to less than 8.5, particularly from 5 to less than 7, by add ing at least one base selected from the group consisting of alkali hydroxides, earth alkali hy droxides and ammonium hydroxide, in particular from the group consisting of NaOH, KOH and NH 4 OH.
  • the base is NaOH.
  • the base is KOH.
  • the base is NH 4 OH.
  • the pH of the reaction mixture is adjusted to a value of 4 to less than 12, more preferably from 4 to less than 11 , most preferably from 4 to less than 10, particularly preferably from 5 to less than 8.5, particularly from 5 to less than 7.
  • the pH of the reaction mixture is adjusted to a value of 5 to 6.99, 5 to 6.9, 5 to 6.5 or 5 to 6.
  • the pH of the reaction mixture is adjusted to a value of 6 to 7.99, 6 to 7.9, 6 to 7.5 or 6 to 7.
  • the pH of the reaction mixture is adjusted to a value of 5 to 7.99, 5.5 to 7.5, or 6 to 7.
  • the pH of the reaction mixture is adjusted to a value of 6 to 8.99, 6.5 to 8.5, or 7 to 8. In another preferred embodi ment, the pH of the reaction mixture is adjusted to a value of 7 to 9.99, 7.5 to 9.5, or 8 to 9. In another preferred embodiment, the pH of the reaction mixture is adjusted to a value of 8 to 10.99, 8.5 to 10.5, or 9 to 10. In another preferred embodiment, the pH of the reaction mixture is adjusted to a value of 9 to 11.99, 9.5 to 11.5, or 10 to 11. In another preferred embodiment, the pH of the reaction mixture is adjusted to a value of 10 to 12, 10.5 to 12, or 11 to 12.
  • the base typically predetermines the counter anion(s) of the salt.
  • the isomers of the reaction product are obtained in the form of an alkali, earth alkali or ammonium salt, in particular in the form of a so dium, potassium or ammonium salt.
  • salts of the isomers of the reaction product include salts wherein the isomers of the reaction product are mono-anions or di-anions, and form a salt with one or two cations including the al kali metal cations, earth alkali metal cations or ammonium cations of the above-mentioned ba ses.
  • the isomers of the reaction product may preferably be obtained in the form of the di sodium, di-potassium or di-ammonium salt or in the form of the mono-sodium, mono-potassium or mono-ammonium salt, both options being covered alone or in combination by defining that the isomers of the reaction product are obtained in the form of the sodium, potassium or ammo nium salt.
  • the isolated aqueous solution comprising the isomers of the reaction product has a pH value of from 4 to less than 12, more preferably from 4 to less than 11 , most preferably from 4 to less than 10, particularly preferably from 5 to less than 8.5, particularly from 5 to less than 7, for example of from 5 to 6.99, 5 to 6.9, 5 to 6.5 or 5 to 6.
  • the isolated aqueous solution comprising the isomers of the reaction product has a pH value of from 6 to 7.99, 6 to 7.9, 6 to 7.5 or 6 to 7.
  • the isolated aqueous solution comprising the isomers of the reaction product has a pH value of from 5 to 7.99, 5.5 to 7.5, or 6 to 7.
  • the iso lated aqueous solution comprising the isomers of the reaction product has a pH value of from 6 to 8.99, 6.5 to 8.5, or 7 to 8.
  • the isolated aqueous solution comprising the isomers of the reaction product has a pH value of from 7 to 9.99, 7.5 to 9.5, or 8 to 9.
  • the isolated aqueous solution comprising the isomers of the reaction product has a pH value of from 8 to 10.99, 8.5 to 10.5, or 9 to 10.
  • the isolated aqueous solution comprising the isomers of the reaction prod uct has a pH value of from 9 to 11.99, 9.5 to 11.5, or 10 to 11.
  • the isolated aqueous solution comprising the isomers of the reaction product has a pH value of from 10 to 12, 10.5 to 12, or 11 to 12.
  • the isomers of the reaction product are ob tained in the aqueous phase in a high purity, preferably in a purity of at least 95 %, and apart from an optional washing step with an organic solvent, no further purification steps are required.
  • the aqueous solutions comprising the isomers of the reaction product may directly be used in a formulation for agricultural applications.
  • MA Maleic acid
  • MAA Maleic acid anhydride
  • FA Fumaric acid
  • the invention in a further aspect relates to an aqueous solution having a pH in the range of from 4 to less than 12 comprising an isomer mixture comprising 2-(3,4-dimethyl-
  • the aqueous solution comprising said isomer mixture has a pH range of from 4 to less than 12, more preferably from 4 to less than 11 , most preferably from 4 to less than 10, particularly preferably from 5 to less than 8.5, particularly from 5 to less than 7.
  • the aqueous solution comprising said isomer mixture has a pH range of from 5 to 6.99, 5 to 6.9, 5 to 6.5 or 5 to 6.
  • the aqueous solu tion comprising said isomer mixture has a pH range of from 6 to 7.99, 6 to 7.9, 6 to 7.5 or 6 to 7.
  • the aqueous solution comprising said isomer mixture has a pH range of from 5 to 7.99, 5.5 to 7.5, or 6 to 7. In another preferred embodiment, the aqueous solution comprising said isomer mixture has a pH range of from 6 to 8.99, 6.5 to 8.5, or 7 to 8.
  • the aqueous solution comprising said isomer mixture has a pH range of from 7 to 9.99, 7.5 to 9.5, or 8 to 9. In another preferred embodiment, the aqueous solution comprising said isomer mixture has a pH range of from 8 to 10.99, 8.5 to 10.5, or 9 to 10. In another preferred embodiment, the aqueous solution comprising said isomer mixture has a pH range of from 9 to 11.99, 9.5 to 11.5, or 10 to 11. In another preferred embodiment, the aqueous solution comprising said isomer mixture has a pH range of from 10 to 12, 10.5 to 12, or
  • the aqueous solution comprises the two isomers in a molar ratio of 5:95 to 95:5, preferably 50:50 to 95:5, more preferably 70:30 to 90:10 and most prefera bly 80:20.
  • the aqueous solution comprises the two isomers in a purity of at least 95 % by weight based on total amount of substances dissolved in the aqueous solu tion.
  • the present invention relates to an isomer mixture comprising 2-(3,4-dime- thyl-1 H-pyrazole-1-yl) succinic acid in the form of an ammonium salt and 2-(4,5-dimethyl-1 H- pyrazole-1-yl) succinic acid in the form of an ammonium salt.
  • the iso mers may each be present in the form of the mono-ammonium salts or in the form of the di-am- monium salts.
  • the present invention relates to an isomer mixture comprising 2-(3,4- dimethyl-1 H-pyrazole-1-yl) succinic acid diammonium salt and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid diammonium salt.
  • process B of the invention preferred embodiments regarding process B of the invention are provided. It is to be understood that the preferred embodiments to be illustrated below of process B of the in vention are to preferred alone or in combination with each other.
  • the present invention relates in a further aspect to a process for preparing an isomer mixture comprising 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof by reacting 3,4-dime- thylpyrazole with fumaric acid in the absence of an organic solvent.
  • the 3,4-dimethylpyrazole is provided as a solid or as an aqueous suspen sion.
  • the fumaric acid is provided as an aqueous suspension. Either the two suspen sions are then mixed, or the 3,4-dimethylpyrazole in solid form is added to the fumaric acid con taining suspension. Alternatively, both starting materials are added in solid form to water, wherein the order of addition may be varied.
  • the reactants 3,4-dimethylpyrazole and fumaric acid are provided in the form of aqueous solutions or suspensions.
  • the molar ratio of the two starting materials may vary from 1.5:1 to 1 :1.5, preferably from 1.2:1 to 1 :1.2.
  • the reaction is preferably performed under stirring.
  • the reaction takes place at a pH of less than 12, more preferably from 4 to less than 11 , most preferably from 4 to less than 10, particularly preferably from 5 to less than 8.5, particularly from 5 to less than 7 due to the acidity of the fumaric acid.
  • Suitable temperatures for reacting 3,4-dimethylpyrazole with fumaric acid are in the range of from 20 ° C to 200 ° C, preferably from 50 ° C to 170 ° C, more preferably from 80 ° C to 170
  • reaction temperature is above 100 ° C, it is to be understood that the reaction will be performed under pressure.
  • the reaction time may vary in broad range, e.g. from 1 hour to 1 day, preferably from 3 to 12 hours, most preferably until complete consumption of fumaric acid.
  • 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof and 2-(4,5-dimethyl-1 H-pyrazole-1-yl) succinic acid or salts thereof are obtained in a molar ratio of 5:95 to 95:5, preferably 50:50 to 95:5, more preferably 70:30 to 90:10 and most preferably about 80:20.
  • the isomers of the reaction product are isolated from an aqueous solution by crystallization.
  • Crystallization of the isomers of the reaction product can be achieved by allowing the reaction mixture to slowly cool until crystallization begins. In order to initiate crystallization or in order to obtain an excess of 2-(3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid crystals, seed crystals of 2- (3,4-dimethyl-1 H-pyrazole-1-yl) succinic acid can be added to the reaction mixture.
  • the obtained crystals may be dried and further purified by recrystallization through taking up the dried crystals in an organic solvent, preferably an ether solvent as defined above, for exam ple in diethylether.
  • the crystals will precipitate and can subsequently be filtered off.
  • the 2-(3,4-dimethyl-1 H-pyrazole) succinic acid or salts thereof can be isolated in high yields of at least 90% and a high purity of at least 95%.
  • Salts can be formed by adding a base to an aqueous solution of the isomers of the reaction product.
  • Suitable bases are selected from the group consisting of alkali hydroxides, earth alkali hydroxides and ammonium hydroxide, in particular from the group consisting of NaOH, KOH and NH 4 OH.
  • the base is NaOH.
  • the base is KOH.
  • the base is NH 4 OH.
  • the isomers of the re action product may then preferably be isolated in the form of the di-sodium, di-potassium or di ammonium salt or in the form of the mono-sodium, mono-potassium or mono-ammonium salt, both options being covered alone or in combination by defining that the isomers of the reaction product are isolated in the form of the sodium, potassium or ammonium salt.
  • the present invention further relates to an aqueous solution obtainable by dissolving the isolated isomers of the reaction product in water and by adjusting the pH to less than 12, more preferably from 4 to less than 11 , most preferably from 4 to less than 10, particu larly preferably from 5 to less than 8.5, particularly from 5 to less than 7, using at least one base selected from the group consisting of alkali hydroxides, earth alkali hydroxides and ammonium hydroxides, in particular from the group consisting of NaOH, KOH and NH 4 OH.
  • the aqueous solution as described above is adjusted to a pH of from 4 to less than 12, preferably of
  • phases were separated at this temperature.
  • the aqueous layer containing the product (iso- meric mixture of 2-(3,4-dimethylpyrazol-1-yl)butanedioic acid and 2-(4,5-dimethylpyrazol-1- yl)butanedioic acid)) as salt, is washed 4 times with each 160 g of cyclohexanone.
  • the combined organic layers contain the unreacted 3,4-dimethylpyrazole and can be recycled to the next batch after concentration by distillation under reduced pressure (35 mbar) and the distilled cyclohexanone-/water-mixture for the extractions in a subsequent batch.
  • the aqueous layer is diluted with 250 g of water and 320 g of water/cyclohexanone-mixture is distilled off at 150 mbar to obtain the product as isomeric salt-mixture with a yield > 95 % and a purity of less than 0.5 % 3,4-dimethylpyrazole.

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Abstract

La présente invention concerne un procédé de préparation d'acide diméthylpyrazole succinique dans un système à deux phases comprenant de l'eau et au moins un solvant organique ou un procédé de préparation d'acide diméthylpyrazole succinique en l'absence d'un solvant organique. En outre, la présente invention concerne des solutions aqueuses d'acide diméthylpyrazole succinique ayant un pH inférieur à 12.
PCT/EP2019/084341 2018-12-21 2019-12-10 Procédé de préparation d'acide 2-(3, 4-diméthyl-1h-pyrazole-1-yl) succinique et d'acide 2-(4, 5-diméthyl-1h-pyrazole-1-yl) succinique dans un système de solvant à deux phases Ceased WO2020126645A1 (fr)

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CN112321508A (zh) * 2020-11-06 2021-02-05 浙江今晖新材料股份有限公司 一种硝化抑制剂的制备方法
CN112358369A (zh) * 2020-11-06 2021-02-12 浙江今晖新材料股份有限公司 一种硝化抑制剂的合成方法

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CN112321508A (zh) * 2020-11-06 2021-02-05 浙江今晖新材料股份有限公司 一种硝化抑制剂的制备方法
CN112358369A (zh) * 2020-11-06 2021-02-12 浙江今晖新材料股份有限公司 一种硝化抑制剂的合成方法

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