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    • 专利摘要:
    The present invention relates to a process for supplying the substituted phenyl ketones in which the Grignard reagent that is obtained from the phenyl bromide is reacted with the acyl chloride at a temperature of -20º C to 10º C. In addition , the present invention relates to the use of substituted phenoxyphenyl ketones obtained through the process of the present invention for the preparation of triazoles.
    公开号:BR112017026791B1
    申请号:R112017026791-8
    申请日:2016-06-14
    公开日:2021-02-23
    发明作者:Joachim Gebhardt；Daniel Saelinger；Manfred Ehresmann；Roland Goetz
    申请人:Basf Agro B.V；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [0001] The present invention relates to a process for providing the substituted phenyl ketones.
    [0002] In addition, the present invention relates to the use of substituted phenoxyphenyl ketones obtained through the process of the present invention for the preparation of triazoles. BACKGROUND OF THE INVENTION
    [0003] The substituted phenyl ketones provided through the process, in accordance with the present invention, are valuable intermediate compounds for the synthesis of triazole compounds that have pesticidal activity, in particular fungicide. The publication WO 2013/007767 refers to the compounds of 1- [4-phenoxy-2- (haloalkyl) phenyl] -2- (1,2,4-triazol-1-yl) ethanol substituted fungicides that can be synthesized by means of a respective intermediate compound of phenyl ketone. The publication WO 2014/108286 (EP 13.150.663.6; PCT / EP 2013 / 077.083), WO 2015/091045 (PCT / EP2014 / 076839) and WO 2016/005211 (EP 14.176.130.4; PCT / EP2015 / 064550) describes the improved process steps and processes in the synthesis of certain triazole compounds active as a fungicide.
    [0004] The methods known from the literature are sometimes not suitable for the effective synthesis of substituted phenyl ketones, since the yield or purity are not sufficient and / or the reaction conditions and parameters, such as temperature, they are not optimal, as they lead to unwanted by-products and / or lower yields. Since said substituted phenyl ketones are valuable intermediates for the synthesis of triazole compounds with promising fungicidal activity, there is a continuing need for improved processes that easily make such intermediates and compounds available. DESCRIPTION OF THE INVENTION
    [0005] An object of the present invention was to provide an improved process for the synthesis of substituted phenyl (II) ketones, which are valuable intermediates for the preparation of triazole compounds active as a fungicide which circumvent the disadvantages of known processes.
    [0006] In particular, it has now been found that reducing the temperature during the reaction to compounds (II) from compounds (III), surprisingly, reduces unwanted by-products drastically and, at the same time, the reaction remain so that the process is industrially valuable.
    [0007] The present invention, therefore, relates to a process for the preparation of ketone compounds
    - where - X is F or Cl and - R1 is C1-C6 alkyl or C3-C8 cycloalkyl; - which comprises the following stage: (1) the reaction of a compound of Formula (III)
    - with R'-Mg-Hal (IV) or Mg, and R1C (= O) Cl (V), - where the temperature during the reaction with (V) is maintained in the range from -20 ° C to 10 ° C, - where - R 'is C1-C4 alkyl or C3-C6 cycloalkyl and - Hal is halogen.
    [0008] In process step (i), according to the present invention, the substituted phenyl compounds of Formula (III) are used, where X is F or Cl.
    [0009] The 2-bromo-5-fluoro / chloro-benzotrifluoride of Formula (III) is reacted with the Grignard R'-Mg-Hal (IV) reagent or magnesium (Mg).
    [0010] According to a preferred embodiment, the Grignard R'-Mg-Hal (IV) reagent is used in the process. The R 'in the Grignard reagent is C1-C4 alkyl or C3-C6 cycloalkyl, in particular, it is selected from methyl, ethyl, isopropyl, tert-butyl, sec-butyl and cyclopropyl. Specifically, R 'in the Grignard reagent is selected from isopropyl, tert-butyl, sec-butyl and cyclopropyl. In a specific embodiment, R 'is isopropyl. In another embodiment, R 'is sec-butyl. Hal is halogen, in particular, Cl or Br. It can also be used superior to a Grignard reagent in the same reaction, such as, for example, reagent (IV), where Hal is Br is Br together with the respective reagent (which has the same R '), where Hal is Cl. According to one embodiment, Hal is the Cl and R 'in the Grignard reagent is selected from isopropyl, tert-butyl, sec-butyl and cyclopropyl. According to another embodiment, Hal is the Br and R 'in the Grignard reagent is selected from isopropyl, tert-butyl, sec-butyl and cyclopropyl. In a preferred embodiment, in the process of the present invention, the Grignard reagent is (isopropyl) -Mg-Cl and / or (iso-propyl) -Mg-Br, in particular, (iso-propyl) - Mg-Cl or (isopropyl) -Mg-Br. In another embodiment, the Grignard reagent contains both, (iso-propyl) -Mg-Cl and (iso-propyl) -Mg-Br. In another preferred embodiment, in the process of the present invention, the Grignard reagent is (sec-butyl) -Mg-Cl and / or (sec-butyl) -Mg-Br, in particular, (sec-butyl) -Mg-Cl or (sec-butyl) -Mg-Br. In another embodiment, the Grignard reagent contains both, (sec-butyl) -Mg-Cl and (sec-butyl) -Mg-Br.
    [0011] Preferably, the Grignard reagent is used in an amount of 1 eq to 2 eq, in particular, from 1.1 to 1.8 eq, more specifically, from 1.2 to 1.6 eq, in relation to to an equivalent of compound (III). In particular, the amounts of 1.3 to 1.5 eq, more especially, 1.2 to 1.4 eq per mole of compound (III) can be favorable according to the present invention. It can also be favorable, if the amounts are from 1 to 1.3 eq, more especially, from 1.1 to 1.2 eq per mole of compound (III). Also preferably, it can be if the amounts are from 1.15 to 1.45 eq, in particular, from 1.15 to 1.35 eq per mole of compound (III). In general, the Grignard reagent is used in excess, preferably in a slight excess.
    [0012] Another embodiment concerns the process of the present invention, in which Mg is used, therefore, forming a Grignard reagent with compound (III) and, therefore, reacting with compound (V). It may be preferable if the Mg is used in an amount slightly less than the compound (III). At present, the same details regarding solvents apply.
    [0013] As is generally known to the person skilled in the art, the structure of a Grignard reagent can be described through the equilibrium called Schlenck. A Grignard reagent is subjected to a solvent-dependent equilibrium between different magnesium compounds. The Schlenck balance for the Grignard reagent used, according to the present invention, can be schematically illustrated as follows:

    [0014] Furthermore, it is believed that solvent molecules, especially ethers, such as diethyl ether or THF, which are normally used for reactions with Grignard reagents, can add to the magnesium of the reagent of Grignard, therefore, forming the etherates.
    [0015] Depending on the solvent used in the reaction, of the present invention, the solvent molecules can therefore be added to the Mg reagents, forming - in the case of the use of ethers - the respective etherates. For general information on Grignard's reagent structures, see also Milton Orchin, Journal of Chemical Education, Volume 66, Number 7, 1999, pages 586 to 588.
    [0016] According to an embodiment of the process of the present invention, LiCl is added to the reaction mixture from step (i). According to an alternative, before placing the Grignard reagent (IV) in contact with the process reagents of the present invention, it is placed together with the LiCl, therefore forming an addition product of R'MgHal • LiCl ( (IV) • LiCl). According to this alternative, ((IV) • LiCl) is then used in step (i). The use of LiCl in conjunction with Grignard reagents, in general, is known in the art, see, for example, Angew. Chem. Int. Ed. 2004, 43, 3,333 and Angew. Chem. Int. Ed. 2006, 45, 159.
    [0017] Grignard (IV) reagents or their addition products with LiCl ((IV) • LiCl) are commercially available or can be prepared according to processes well known to the person skilled in the art (see Angew. Chem. Int Ed. 2004, 43, 3,333).
    [0018] In carbonyl chloride (acid chloride) R1C (= O) Cl (V), as well as in other compounds that have this variable, such as (II), (IA), (IB) and (IC), R1 is C1-C6 alkyl or C3-C8 cycloalkyl, in particular, selected from CH3, CH (CH3) 2 and cyclopropyl.
    [0019] According to one embodiment, R1 is C1-C6 alkyl, more specifically, C1-C4 alkyl, in particular, selected from CH3, C2H5, n-C3H7, CH (CH3) 2, n-butyl , iso-butyl and tert-butyl, more especially, selected from CH3, C2H5, CH (CH3) 2 and C (CH3) 3, even more especially from CH3 or CH (CH3) 2. In an especially preferred embodiment, R1 is CH3. According to another embodiment, R1 is C3-C8 cycloalkyl, in particular, C3-C6 cycloalkyl, such as C3H5 (cyclopropyl), C4H7 (cyclobutyl), cyclopentyl or cyclohexyl. An additional embodiment concerns the compounds, where R1 is C3H5 (cyclopropyl) or C4H7 (cyclobutyl), more specifically, cyclopropyl.
    [0020] Carbonyl chloride (acid chloride) R1C (= O) Cl (V) is preferably used in an equimolar amount or in excess compared to the reagent of Formula (III). Specifically, carbonyl chloride (acid chloride) is used in an amount of 1 eq to 3 eq, in particular, 1.1 to 2.5 eq, more specifically, 1.2 to 2 eq, in relation to to an equivalent of compound (III). In particular, the amounts of 1.3 to 1.8 eq, more specifically, 1.4 to 1.6 eq per mole of compound (III) can be favorable according to the present invention. In general, carbonyl chloride (acid chloride) is used in excess, preferably in a slight excess.
    [0021] Grignard's reagent is added in the manner that is common to the technician on the subject. In particular, it can be added as a solution in a suitable solvent such as tetrahydrofuran (THF), 1,4-dioxane, diethyl ether and 2-methyl-tetrahydrofuran.
    [0022] Examples of suitable solvents for step (i) of the process of the present invention are aprotic organic solvents, such as, for example, diethyl ether, tetrahydrofuran (THF), methyl tert-butyl ether (MTBE ), toluene, orthoxylene, meta-xylene, para-xylene and their mixtures. Normally, the Grignard reagent is added as a solution in THF, 1,4-dioxane, diethyl ether or 2-methyl-tetrahydrofuran (2-Me-THF), in particular in THF or diethyl ether, in the reaction vessel or in the vial containing reagent (III) and a solvent such as, for example, toluene, MTBE, orthoxylene, metaxylene, para-xylene, mesylene and / or diisopropyl ether, in particular toluene, MTBE and / or orthoxylene .
    [0023] The temperature for the reaction of the Grignard reagent in step (i) can be from -20 ° C to 70 ° C and, preferably, it is maintained at a maximum of 50 ° C, in particular, at a maximum of 40 ° C, more preferably, to a maximum of 35 ° C. In general, preferably, it is to have a reaction temperature of 20 ° C to 45 ° C, in particular, the ambient temperature at 45 ° C, in particular, between 25 ° C and 40 ° C. In another embodiment, the temperature is 20 ° C to 35 ° C, specifically, 25 ° C to 30 ° C.
    [0024] Within the scope of the present invention, it has been found that the ideal temperature range during the reaction with the reagent R1C (= O) Cl (V) is -20 ° C to 10 ° C. In particular, according to a specific embodiment of the present invention, the temperature is maintained at -15 ° C to 5 ° C, more specifically, at -10 ° C to -5 ° C.
    [0025] It can be preferably, if a Cu (I) catalyst is added in step (i). In particular, the Cu (I) catalyst may preferably be present for the reaction with the reagent (V). A Cu (I) catalyst suitable for the process of the present invention is a Cu (I) salt or a Cu (I) oxide, in particular a Cu (I) salt such as Cu (I) Cl or Cu (I) Br or any of their mixtures. According to a specific embodiment, Cu (I) Cl.
    Accordingly, according to one embodiment, the 2-bromo-5-fluoro / chloro-benzotrifluoride of Formula (III) is reacted with the Grignard reagent R'-Mg-Hal (IV) or magnesium (Mg) and acyl chloride R1C (= O) Cl (V) in the presence of a Cu (I) catalyst in an amount of 0.005 to 0.065 molar equivalents per 1 mol of compound (III). See also publication WO 2015/091045 (PCT / EP 2014 / 076.839).
    [0027] It can be preferably, if 0.005 to 0.055 molar equivalents are used per 1 mol of compound (III). In particular, the Cu (I) catalyst is added in an amount of 0.005 to 0.045 molar equivalents per 1 mol of compound (III). In addition, it may preferably be used if 0.055 to 0.045 molar equivalents per 1 mol equivalent (III), more specifically, 0.005 to 0.04 molar equivalents per 1 mol compound (III). In particular, the amount of Cu (I) catalyst is from 0.01 to 0.03 molar equivalents per 1 mol of molecular weight III, more especially from 0.015 to 0.025 molar equivalents, even more especially from 0.015 to 0, 02 per 1 mole of compound III, specifically, from 0.018 to 0.023 molar equivalents per 1 mole of compound (III). According to one embodiment, the Cu (I) catalyst is added in several portions to the reaction mixture, for example, in two portions at half the total amount.
    [0028] A suitable reaction course is such that the Grignard reagent is first reacted with the compound of Formula (III) and then this reaction mixture is added to the carbonyl chloride (acid chloride) and a Cu (I) portion, in particular half of the total amount of the Cu (I) catalyst. After about half of the Grignard mixture was added to the carbonyl chloride (acid chloride) reaction mixture, the remaining amount of Cu (I) was added. According to another embodiment, the total amount of Cu (I) catalyst is added in one portion.
    [0029] According to yet another preferred embodiment, the Cu (I) catalyst and part of the acid chloride (such as from 0.5% to 10%, more specifically, from 2% to 6%, in particular , up to 5%) and the solvent are added first, and then the remaining acid chloride and the Grignard mixture (prepared from the Grignard reagent and the compound of Formula (III)) are added simultaneously.
    [0030] According to another embodiment, the acid chloride is gradually added to the Cu (I) catalyst and to the reaction mixture of the Grignard reagent and the compound of Formula (III).
    [0031] After step (i), a processing of the reaction mixture can be carried out using procedures generally known to the person skilled in the art. For example, after completing the reaction, water was added. Sometimes, it is possible to add the reaction mixture to the water after the completion of the reaction followed by further respective processing. Instead of water, aqueous acidic solutions can be used and added to the reaction mixture or, conversely, preferably if the reaction mixture is added to the acidic solution.
    [0032] Then, the organic phases are washed with water and the solvent is removed from the separate organic phases.
    [0033] In addition, it may be appropriate to wash the organic phases with the acidic or basic aqueous solution, instead, or in addition to washing with water.
    [0034] The crude product obtained in this way can be used directly in the next process step, that is, the process step (ii), of the present invention. However, the crude product can also still be processed and / or purified as, in general, known to the person skilled in the art. If this is considered appropriate, the reaction mixture is extracted with a suitable organic solvent (for example, aromatic hydrocarbons, such as toluene and xylenes) and the residue, if appropriate, is purified by recrystallization and / or chromatography. By means of the process of the present invention, undesirable by-products, such as cleavage products resulting from the solvent (s) used and / or their derived by-products, can be avoided. For example, if THF is used as a solvent, such unwanted by-products can occur. The type of by-products that is observed still depends on the compound Mg (IV) and the acylation reagent (V) used. Consequently, a wide advantage of the process of the present invention is that less by-products occur that can disrupt the following synthesis steps. In general, through the process of the present invention, the selectivity of the reaction is increased. At the same time, however, the reaction time also remains adequate. In particular, it is prevented according to the process of the present invention, that high amounts of one and the same by-product are formed. In general, it is unfavorable if a relatively high percentage of a special undesirable by-product is formed. Separation is difficult and, as a result, by-products can produce other unwanted by-products in the following steps of the process. When carrying out the process step of the present invention (i), it is possible that each secondary product is present in an amount not exceeding 5% (5% or less), in particular, equal to or less than 2%.
    [0035] According to another embodiment of the present invention, in step (i) no AlCl3 is added to the reaction. Consequently, the reaction is carried out in the absence or, at least, essentially without AlCl3. In particular, a maximum of traces of AlCl3 are present, such as a maximum of 0.0065 mol% of AlCl3, for example, traces due to impurities in other reagents.
    [0036] The starting compounds (III) for the process of the present invention can be synthesized as is known to the person skilled in the art, in analogy with similar known syntheses or is also partially commercially available. See, in particular, publication WO 2013/007767 and its citations contained therein. In the publication WO 2014/108286 favorable details of the process are outlined. See also JACS 1965, 87, page 1353ff, Heterocycles 8, 1977, page 397 ff, Synth. Communications, 15, 1985, page 753, J. Agric. Food Chem. 2009, 57, 4,854-4,860 and DE 3,733,755.
    [0037] The process of the present invention leads to compounds (II) which are valuable intermediates for the synthesis of fungicidal triazole compounds. The following describes a possible route of synthesis for such fungicides using said intermediates (II):
    [0038] Consequently, the present invention also relates to a process for the preparation of triazole compounds of Formula (IC)
    - wherein R1 is defined and preferably defined herein or, according to claims 1 to 7, and - R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl , C3-C8-cycloalkyl-C1-C6-alkyl, phenyl, phenyl-C1-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl; - where the aliphatic portions of R2 are not yet replaced or carry one, two, three or even the maximum possible number of identical or different R12a groups that, independently, are selected from: - R12a is the halogen, OH, CN , nitro, C1-C4 alkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl and C1-C4 haloalkoxy; - where the cycloalkyl and / or phenyl portions of R2 are not yet replaced or carry one, two, three, four, five or even the maximum number of R12b groups, identical or different that are independently selected from: - R12b is halogen, OH, CN, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl and C1-C4 haloalkoxy; and - R4 is the F or Cl - which comprises the following steps: (i) according to the present invention, as described above and according to claims 1 to 9; (ii) the reaction of compound (II) as defined in step (i) with a phenol derivative of Formula (VI)
    - where - R '' is hydrogen or an alkali metal cation, for example, Li +, Na + or K +, in particular, Na +; - in the presence of a base, if R '' is hydrogen resulting in a Formula (IA) ketone
    - (iii) the reaction of the Formula (IA) ketone as defined in step (ii) for oxirans (IB);
    (iv) the reaction of oxirane (IB) as defined in step (iii) with 1H-1,2,4-triazole in the presence of a base to obtain compounds (IC), where R2 is hydrogen (compounds IC -1); - and, to obtain compounds in which R2 is different from hydrogen (compounds IC-2): (v) the derivation of the compound of Formula (IC-1) as defined in step (iv) under basic conditions with R2-LG , where LG is a nucleophilically substitutable leaving group; to result in compounds (IC-2).
    [0039] According to step (ii), compounds (II) are reacted with a phenol of Formula (VI) in the presence of a base.
    [0040] R '' in Formula (VI) is hydrogen ((VI) is a substituted phenol) or an alkali metal structure ((VI) is a substituted phenolate) .R4 in Formula (VI) and Formulas (IA) , (IB) and (IC), respectively, is F or Cl, in particular, Cl.
    [0041] As described above, compound (II) can be used directly from step (i) without further purification or can be used in purified form.
    [0042] Examples of suitable solvents for step (ii) of the process of the present invention are aprotic organic solutions such as, for example, dimethylformamide (DMF), N-methyl pyrrolidone (NMP), dimethyl imidazolidinone (DMI ), toluene, o-xylene, dimethylactamide (DMA) and any mixtures thereof. In particular, DMF, NMP, toluene and DMA or any mixtures, more specifically, DMF, are especially suitable.
    [0043] According to one embodiment, the solvent used in step (ii) does not contain an amount greater than 8 eq of DMF in relation to 1 eq of the phenol of Formula (VI), in particular, not more than 7 eq at 1 eq of the Formula (VI) phenol, more specifically, not exceeding 6 eq to 1 eq of the Formula (VI) phenol. It can be preferably if not more than 7.5, specifically not more than 6.5 eq of DMF are used in the process of the present invention.
    [0044] It may preferably be, if the solvent used in step (ii) does not contain an amount greater than 3 eq of DMF in relation to 1 eq of the phenol of Formula (VI), in particular, not greater than 2.8 eq to 1 eq of the Formula (VI) phenol, more specifically, not exceeding 2.6 eq to 1 eq of the Formula (VI) phenol. It may preferably be, if not more than 2.4 eq, specifically not greater than 2.2 eq of DMF are used in the process of the present invention.
    [0045] The base used in step (ii), preferably, is an inorganic base, according to an embodiment selected from NaOH, KOH, Na2CO3 and K2CO3, more specifically, from Na2CO3 and K2CO3. According to a special embodiment, Na2CO3 is used. According to another special embodiment, K2CO3 is used.
    [0046] The base can be used in solid form or as a solution, for example, as the aqueous solution.
    [0047] The reagents for step (ii) are preferably added at room temperature and the reaction temperature is then raised, in which the reaction temperature after the addition of the reagents is preferably maintained at a maximum of 150 ° C, in particular a maximum of 140 ° C, more preferably a maximum of 130 ° C. In general, preferably, it is to have a reaction temperature of 20 ° C to 135 ° C, in particular 50 ° C to 135 ° C, more especially, 100 ° C to 130 ° C. For example, when using 4-chlorophenol as the phenol derivative of Formula (VI) it may be favorable if (VI) is handled as a solution in a solvent such as DMF.
    [0048] According to another embodiment, the phenol derivative of Formula (VI) (such as 4-chlorophenol) is added as a melt, in which the reaction temperature is then increased as detailed above after the addition of the reagents.
    [0049] After step (ii), a processing of the reaction mixture can be performed using procedures generally known to the person skilled in the art. In general, water was added and the aqueous phase was extracted with a suitable solvent, for example, toluene or o-xylene. The crude product obtained after evaporation of the solvent (s) can be used directly in an additional step, if desired. However, the crude product can also still be processed and / or purified as, in general, known to the person skilled in the art.
    [0050] According to one embodiment, after the completion of the reaction, most of the solvent (for example, DMF or toluene) is removed from the reaction mixture, preferably under reduced pressure. Then, a suitable organic solvent, such as, for example, toluene or o-xylene, is added together with water. According to the process of the present invention, it may be favorable to perform one to three, preferably two, extractions of the aqueous phase.
    [0051] In process step (iii), to obtain an oxirane from the keto group, the compound (IA) is preferably reacted with a trimethylsulf (ox) onide ((CH3) 3S + (O) Hal halide -) (VII) or trimethylsulfonium methyl sulfate of Formula (VIII) (CH3) 3S + CH3SO4-.
    [0052] According to one embodiment, in the process step (iii), the ketone (IA) is reacted with the trimethylsulfonium methyl sulfate of Formula VIII (CH3) 3S + CH3SO4-, preferably in aqueous solution in the presence of a base.
    [0053] The step (iii) for the preparation of oxiranes (IB) especially is as follows: (111) of the reaction of an oxo compound of Formula (IA) with the trimethylsulfonium methyl sulfate of Formula VIII - VIII - (CH3 ) 3S + CH3SO4- - in aqueous solution in the presence of a base, in which the variables R1, R4 are defined as provided and preferably described herein for compounds (IA).
    [0054] In this step of the process (iii) using the trimethylsulfonium methyl sulfate of Formula VIII, preferably, 1 to 4 equivalents are used, in particular, from 1.2 to 3.5 eq, more specifically, from 1 , 5 to 3.3 eq, of water in relation to an equivalent of the compound (IA). It can be favorable, if greater than 1.5 eq of water, in particular greater than 1.5 eq of water for 4 eq of water, more specifically greater than 1.5 eq to 3.5 eq of water, even more especially higher to 1.5 eq of water to 2.5 eq of water per mole of compound (IA) are used. In particular, the proportions from 1.6 to 3.8, more specifically from 1.7 to 3.3 eq, more specifically, from 1.8 to 2.8 eq or, from 1.9 to 2.5 of water per mol of compound (IA) can be favorable according to the present invention. According to another embodiment, greater than 1.5 eq of water, in particular, greater than 2 eq of water, more specifically, greater than 2.5 eq of water per mole of compound (IA) are used. In particular, from 1.6 to 5, more specifically, from 1.7 to 4 eq, more specifically, from 1.8 to 3.5 eq of water per mole of compound (IA) can be favorable according to the present invention.
    [0055] Reagent VIII is preferably used in an amount of 1.1 to 2.5, in particular, from 1.2 to 2, more specifically, from 1.3 to 1.6 equivalents of VIII per 1 equivalent (mol) of the compound (IA).
    [0056] In general, the Formula VIII reagent can be prepared from dimethyl sulfide and dimethyl sulfate. According to one embodiment, reagent VIII is prepared in situ by adding dimethyl sulfate to the reaction mixture containing dimethyl sulfide. According to another embodiment, the dimethyl sulphide or dimethyl sulphate is loaded first and the other reagent is then added, in which it may be preferably to add the dimethyl sulphide to a reaction mixture containing dimethyl sulfate. Dimethyl sulfide is normally used in excess. In particular, dimethyl sulfide, in general, is used in quantities so that reagent VIII is sufficiently formed during the reaction. The molar ratio between dimethyl sulfide and dimethyl sulfate for the formation of reagent VIII is from 1: 1 to 2: 1. Preferably, the molar ratio between dimethyl sulfide and dimethyl sulfate is from 1: 1 to 1.5: 1, more preferably from 1: 1 to 1.4: 1. It may also preferably be used from 1 to 1.3, in particular from 1 to 1.25, more specifically, from 1 to 1.1 eq of dimethyl sulfide with respect to a dimethyl sulfate equivalent.
    [0057] Preferably it is the use as reagent VIII, of an aqueous solution of trimethylsulfonium methyl sulfate containing from 33 to 37% by weight, preferably from 34 to 36% by weight, more specifically, from 34 to 35 , 3% by weight, also more specifically, from 34.3 to 35.9% by weight, of trimethylsulfonium cation.
    [0058] In particular, reagent solution VIII contains from 33 to 37% by weight, preferably from 34 to 36% by weight, more specifically, from 34 to 35.3% by weight, also more specifically, from 34 , 3 to 35.9% by weight, of trimethylsulfonium cation. Therefore, the amount of trimethylsulphonium methyl sulfate in the reagent, measured as the sum of trimethylsulphonium cation and methylsulphate anion, is about 80 to 90% by weight, preferably about 83 to 88% by weight , more specifically, from about 83 to 86% by weight. Quantification, for example, can be performed using quantitative NMR spectroscopy.
    [0059] The viscosity of the aqueous reagent VIII solution is comparatively low. The solutions are stable at room temperature, in particular at 25 ° C, and can be stored for a longer period. In particular, the reagent solution does not crystallize during storage for a longer period, such as several weeks, for example, up to 12 weeks, at temperatures of 10 to 25 ° C.
    [0060] The reagent can be prepared by adding dimethyl sulfate to the water and dimethyl sulfide. Dimethyl sulfide is normally used in excess, in general, from 2 to 8, more preferably from 4 to 6, more specifically, from 4.5 to 5.5, equivalents.
    [0061] In the preparation of the aqueous solution of reagent VIII, in particular, from 0.8 to 2.2 eq, more preferably, they are from 0.9 to 1.2 eq, water in relation to dimethyl sulfate are used. It can also be preferably if in the preparation of the aqueous solution of reagent VIII, preferably from 1.3 to 2.2 eq, more preferably from 1.45 to 2.0 eq of water in relation to dimethyl sulfate. used.
    [0062] Preferably, the temperature of the reaction mixture, when adding dimethyl sulfate, is at room temperature, in particular, from 25 ° C to 40 ° C.
    [0063] The aqueous reagent is separated as the lower phase and can be used more as such.
    [0064] The use of the reagent VIII aqueous solution has been proven to be very efficient also for the stepped reaction conditions, since it is stable and since it contains a defined amount of reagent, so that reagent VIII can be easily dosed and precision in the reaction mixture.
    [0065] Therefore, it is a preferred embodiment, if reagent VIII is added as an aqueous solution of trimethylsulfonium methyl sulfate containing from 33 to 37% by weight, preferably from 34 to 36% by weight, more specifically , from 34 to 35.3% by weight, also more specifically, from 34.3 to 35.9% by weight of trimethylsulfonium cation.
    [0066] According to an embodiment of the process of the present invention, dimethyl sulfide is also used as a solvent in step (iii). According to another embodiment, an additional solvent is used. In particular, an aprotic organic solvent is suitable, such as, for example, diethyl ether, methyl tert-butyl ether, chlorobenzene, xylene or toluene.
    [0067] The base that can be used in step (iii) is preferably selected from KOH and NaOH. In a preferred embodiment, KOH is used, preferably as pellets or solid flakes. It is preferably, if at least 3 equivalents of base, preferably at least 3.2 eq, more specifically, at least 3.4 eq per 1 equivalent of compound (IA) are used. It can be preferably if the amount of base is 3 to 6 eq, more specifically, 3 to 5 eq per mole of compound (IA).
    [0068] The reaction temperature, when adding KOH in step (iii) preferably, is maintained at a maximum of 60 ° C, more specifically at a maximum of 50 ° C. In general, also preferably, it is to have a reaction temperature when adding the KOH of at least 20 ° C, in particular, at least at room temperature, in particular, at least 25 ° C. In another embodiment, the temperature is at least 30 ° C. It can preferably be, if the temperature is at least 35 ° C or at least 45 ° C. The temperature of the reaction mixture, for example, can be maintained at these intervals by adding KOH in portions.
    [0069] The overall reaction temperature in step (iii) is preferably maintained at a maximum of 70 ° C, in particular, at a maximum of 60 ° C, most preferably at a maximum of 50 ° C. In general, it is also preferable to have a reaction temperature of at least 20 ° C, in particular at least room temperature, in particular at least 25 ° C. In another embodiment, the temperature is at least 30 ° C. It can be preferably, if the temperature is at least 35 ° C.
    [0070] In case the reaction mixture is processed after step (iii) is suitable, it can be carried out using procedures generally known to the person skilled in the art. It may preferably be, if water is added to the reaction mixture after the completion of step (iii) and the resulting mixture is heated while stirring depending on the melting point of the organic content. The temperature during this heating is preferably maintained from 30 ° C to 70 ° C, more specifically from 40 ° C to 60 ° C, even more specifically from 50 ° C to 60 ° C. The organic phase, for example, can be separated and dissolved in a suitable solvent such as dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO) or dimethylacetamide (DMAC). Dimethyl sulfide, if still present, is preferably removed by distillation before or after the addition of the solvent. The reaction mixture can then be used directly for the next step or, if appropriate, further processed and / or purified, for example, through recrystallization and / or chromatography.
    [0071] According to another specific embodiment, in step (iii), the oxo compound of Formula (IA) is reacted with dimethyl sulfide (CH3) 2S and dimethyl sulfate (CH3) 2SO4, forming reagent VIII , trimethylsulfonium methyl sulfate [(CH3) 3S + CH3SO4-], in aqueous solution in the presence of potassium hydroxide (KOH), in which dimethyl sulfide and dimethyl sulfate are used in a molar ratio of 1: 1 to 2 : 1 and in which a maximum of 10% by weight of organic solvent in relation to the amount of compound (IA), are added. For details, see also publication WO 2016/005211 (PCT / EP 2015 / 064.550; EP 14.176.130.4). In this embodiment, the Formula VIII reagent is formed from dimethyl sulfide and dimethyl sulfate. In particular, reagent VIII is prepared in situ. Dimethyl sulfide or dimethyl sulfate is first loaded and the other reagent is then added. It may be preferable to add the dimethyl sulfide to a reaction mixture containing the dimethyl sulfate.
    [0072] Dimethyl sulphide and dimethyl sulphate are preferably used in quantities such that reagent VIII is present in the reaction mixture in an amount of 1.1 to 2.5, in particular 1, 2 to 2, more specifically, from 1.3 to 1.6 equivalents of VIII per 1 equivalent (mol) of the compound (IA).
    [0073] Dimethyl sulfide is used in quantities so that reagent VIII is sufficiently formed during the reaction. The molar ratio between dimethyl sulfide and dimethyl sulfate for the formation of reagent VIII is from 1: 1 to 2: 1. Preferably, the molar ratio between dimethyl sulfide and dimethyl sulfate is from 1: 1 to 1.5: 1, more preferably from 1: 1 to 1.4: 1. It can also preferably be used from 1 to 1.3, in particular from 1 to 1.25, more specifically, from 1 to 1.1 of dimethyl sulfide with respect to an equivalent of dimethyl sulfate.
    [0074] This reaction step can be carried out with a maximum of 10% by weight of organic solvents in relation to the amount of compound (IA) [amount of solvent: (amount of solvent + amount of compound III)]. In particular, the reaction can be carried out using a maximum of 8% by weight, more specifically, a maximum of 5% by weight, even more specifically, a maximum of 3% by weight, of organic solvents in relation to the amount of compound (IA). More specifically, in the reaction mixture, a maximum of 2% by weight, more specifically, a maximum of 1% by weight of organic solvents in relation to the amount of compound (IA) are added.
    [0075] In a specific embodiment, in this step (iii), essentially no organic solvent is added. In particular, in step (iii), no organic solvent separated from the reagents used is added.
    [0076] Organic solvents are liquid organic compounds that dilute reagents without participating in the reaction or catalyzing the reaction. The person skilled in the art of organic synthesis is familiar with "organic solvents" and it is evident to the person skilled in the art what types of solvents are "organic solvents". Examples for organic solvents, for example, are alcohols, nitriles and aromatic hydrocarbons. The alcohols, for example, are methanol, ethanol, propanol and butanol (for example, tert-butanol). Aromatic hydrocarbons, for example, are toluene or xylenes. An example for nitrile is acetonitrile.
    [0077] The reaction step (iii) is preferably carried out in an aqueous solution. Preferably, water is used in an amount of 0.5 to 4 eq, in particular, 0.9 to 4, in relation to an equivalent of the compound (IA). According to one embodiment, relatively low amounts of water are used, for example, from 0.5 to 0.95 eq, more specifically, from 0.6 to 0.94, even more specifically, from 0.7 to 0 , 93 eq with respect to a compound equivalent (IA). It can also be advantageous to use from 0.8 to 0.92 eq, more specifically, from 0.85 to 0.91, even more specifically, from 0.85 to 0.9 eq in relation to an equivalent of the compound (IA) in the process of the present invention. According to another embodiment, 0.9 to 4 equivalents are used, more specifically, from 1 to 4, in particular, from 1.2 to 3.5 eq, more specifically, from 1.5 to 3.3 eq , of water in relation to an equivalent of the compound (IA). It can be favorable, if greater than 1.5 eq of water, in particular, greater than 1.5 eq of water to 4 eq of water, more specifically, greater than 1.5 eq to 3.5 eq of water, even more especially, greater than 1.5 eq of water to 2.5 eq of water per mole of compound (IA) are used. In particular, the proportions of 1.6 to 3.8, more specifically, from 1.7 to 3.3 eq, more specifically, from 1.8 to 2.8 eq or 1.9 to 2.5 of water per mol of compound (IA) can be favorable according to the present invention. In another special embodiment, the advantages can be achieved if the amounts of water used in step (iii) are 0.5 to 0.95 eq or greater than 1.5 eq of water to 4 eq per mole of compound (IA ).
    [0078] In step (iii), preferably KOH is used. It is preferably, if at least 2 equivalents of base, more specifically, at least 2.5 equivalents of base, and more specifically, at least 3 equivalents of base per 1 equivalent of compound (IA) are used. It can be preferably, if at least 3.2 eq, more specifically, at least 3.4 eq per 1 equivalent of compound (IA) are used. In addition, it can be advantageous if the base amount is 2 to 6 eq, in particular 2.5 to 5.5 eq, more specifically, 2.5 to 5 eq, even more specifically, 3 to 5 eq per mole of compound (IA).
    [0079] KOH, in particular, is used in solid form, preferably as solid pellets, flakes, micropills and / or powder.
    [0080] The base, especially the solid KOH, is specially used in such a way that the preference range of water present in the reaction is maintained. Then, part of the base is dissolved in the reaction solution and some is still present in the solid form during the reaction.
    [0081] KOH can be added in one or more portions, for example, from 2 to 8 portions, to the reaction mixture. KOH can also be added continuously. Preferably, KOH is added after the compound (IA) is loaded into the reaction vessel. However, the order can also be changed and the compound (IA) is added to the reaction mixture that already contains KOH.
    [0082] The order of addition of reagents to the reaction mixture is variable. In one embodiment, the base is added to the compound (IA) solution and the solvent is added first, and then reagent VIII. According to another embodiment, reagent VIII is added first to the compound (IA) solution, and then the base is added. According to another embodiment, a solution of compound (IA) and reagent VIII are added simultaneously to the base. In the last embodiment, the base is preferably suspended in a sufficient solvent and is stirred during the addition of the reagents.
    [0083] Oxirans (IB) can still be reacted with a triazole of Formula (IC), as defined above.
    [0084] LG represents a nucleophilically replaceable removable group, such as halogen, alkylsulfonyl, alkylsulfonyloxy and arylsulfonyloxy, preferably chlorine, bromine or iodine, especially preferably bromine.
    [0085] According to one embodiment, R2 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8-cycloalkyl C1-C4 alkyl, phenyl, phenyl-alkyl C1-C4, C2-C4 phenyl-alkenyl and C2-C4 phenyl-alkynyl, where R2, in each case, is unsubstituted or is replaced by R12a and / or R12b, as defined and preferably defined herein.
    [0086] According to another embodiment, R2 is C1-C6 alkyl, in particular C1-C4 alkyl, such as CH3, C2H5, CH (CH3) 2, CH2CH2CH3, CH2CH2CH2CH3, CH2CH (CH3) 2. An additional embodiment concerns the compounds, where R2 is C1-C6 alkyl, in particular C1-C4 alkyl, which is replaced by one, two or three or up to the maximum possible number of identical or different R12a groups, as defined and preferably defined herein. According to yet another embodiment, R2 is C3-C8-C1-C6-cycloalkyl, in particular, C3-C6-C1-C4-cycloalkyl. Another embodiment concerns compounds, wherein R2 is C3-C8-C1-C6-cycloalkyl, in particular, C3-C6-C1-C4-cycloalkyl, more especially, C3-C6-C1-C2-cycloalkyl , which is replaced by one, two or three or up to the maximum possible number of R12a groups, identical or different, in the alkyl portion and / or replaced by one, two, three, four or five or up to the maximum possible number of R12b groups , identical or different, in the cycloalkyl portion. R12a and R12b, in each case, are as defined and preferably defined herein.
    [0087] According to another embodiment, R2 is C2-C6 alkenyl, in particular, C2-C4 alkenyl, such as CH2CH = CH2, CH2C (CH3) = CH2 or CH2CH = CHCH3. Another embodiment concerns compounds, where R2 is C2-C6 alkenyl, in particular, C2-C4 alkenyl, which is replaced by one, two or three or up to the maximum possible number of identical or different R12a groups, as defined, and preferably defined herein. According to a specific embodiment, R2 is C2-C6 haloalkenyl, in particular, C2-C4 haloalkenyl, such as CH2C (Cl) = CH2 and CH2C (H) = CHCl. According to yet another embodiment, R2 is C2-C6 alkynyl, in particular, C2-C4 alkynyl, such as CH2C CH or CH2C CCH3. Another realization concerns the compounds, where R2 is C2-C6 alkynyl, in particular, C2-C4 alkynyl, which is replaced by one, two or three or up to the maximum possible number of identical or different R12a groups, as defined and preferably defined herein.
    [0088] According to yet another embodiment, R2 is C3C8 cycloalkyl, especially C3-C6 cycloalkyl, such as C3H5 (cyclopropyl), C4H7 (cyclobutyl), cyclopentyl or cyclohexyl. An additional embodiment concerns the compounds, where R2 is C3-C8 cycloalkyl, in particular, C3-C6 cycloalkyl, such as C3H5 (cyclopropyl) or C4H7 (cyclobutyl), which is replaced by one, two, three four or five or even the maximum number of R12b groups, identical or different, as defined and preferably defined herein. In another embodiment of the present invention, R2 is selected from C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, where R2, in each case, is unsubstituted or is replaced by R12a and / or R12b as defined and preferably defined herein. In each case, the substituents may also have the meanings of preference for the respective substituent, as defined above.
    [0089] R12a, according to the present invention, preferably independently is selected from F, Cl, OH, CN, C1-C2 alkoxy, cyclopropyl, 1-F-cyclopropyl, 1-Cl-cyclopropyl and haloalkoxy C1-C2.
    [0090] R12b, according to the present invention, preferably independently is selected from F, Cl, OH, CN, nitro, CH3, OCH3, cyclopropyl, 1-F-cyclopropyl, 1-Cl-cyclopropyl and halomethoxy.
    [0091] In an embodiment of the present invention, in the process step (iv) an inorganic base is used.
    [0092] The inorganic base that can be used in step (iv) is preferably selected from NaOH, KOH, Na2CO3 and K2CO3, more specifically, from NaOH and KOH. According to one embodiment, NaOH was used. According to another embodiment, KOH was used.
    [0093] According to a specific embodiment, the sodium salt of 1H-1,2,4-triazole as a base is used, wherein said sodium salt is prepared using the triazole and a base, preferably selected from of NaOH, NaH and Na-alcoholates. See also patent DE 3,042,302.
    [0094] The amount of base used in step (iv) is preferably less than or equal to 1 eq, in particular less than 1 eq, more preferably equal to or less than 0.8 eq, even more preferably , equal to or less than 0.6 equivalents per 1 equivalent of compound (IB). Also, preferably, the base amounts are equal to or less than 0.4 equivalents, in particular, equal to or less than 0.2 equivalents, specifically, equal to or less than 0.1 eq per 1 equivalent of compound (IB). Preferably, at least 0.1 eq is used, more preferably at least 0.2 equivalents, in particular at least 0.3, more specifically, at least 0.4 eq of base per 1 equivalent of the compound (IB).
    [0095] It can be favorable, if, in the synthesis of (IC-1), less than 1 eq of base is used in relation to the compound (IB). In its specific embodiments, NaOH is preferably used as a base in an amount as provided above, in particular, in an amount of 0.1 to 0.55 eq in relation to the Formula (IB) oxirane.
    [0096] In order to preferably have lower reaction times, temperatures of at least 100 ° C, more preferably of at least 110 ° C, in particular of at least 120 ° C, are favorable. It is also an accomplishment for refluxing the reaction mixture. Preferably, the reaction temperature is not more than 150 ° C, in particular, not more than 140 ° C. Specifically, a reaction temperature of 120 ° C to 140 ° C is used.
    [0097] The amount of 1H-1,2,4-triazole used in step (iv), in general, is at least 1 eq per mole of oxirane (IB). According to one embodiment, 1H-1,2,4-triazole is used in excess of oxirane (IB). Preferably they are greater than 1 eq to 2 eq, more preferably, greater than 1 eq to 1.8 eq, more preferably still, greater than 1 eq to 1.6 eq. Mainly for economic reasons, it may be preferable to use at least 1.1 eq, specifically, from 1.15 eq, to 1.5 eq of triazole in relation to oxirane (IB).
    [0098] The solvent used in step (iv) is preferably selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone. Most preferably, it is dimethylformamide.
    [0099] According to a preferred embodiment, the compounds (IC-1) resulting from step (iv) are crystallized from a suitable solvent such as, for example, toluene, an aliphatic alcohol, acetonitrile, ethyl acetate and / or cyclohexane, in particular toluene and / or an aliphatic alcohol.
    [0100] In general, an unwanted by-product in the synthesis of IC-1 compounds that can occur in unwanted amounts is the symmetrical ICs-1 triazole which is formed together with the desired Formula IC-1 triazole, therefore, leading to lower yields of the desired product.

    [0101] Accordingly, according to a preferred embodiment of the present invention, the products resulting from step (iv) are crystallized from a suitable solvent. This stage is called the final processing stage (iv-1). Suitable solvents, for example, are selected from toluene, an aliphatic alcohol, acetonitrile, carbonic acid ester and cyclohexane, or any of their mixtures, in particular toluene, an aliphatic alcohol and carbonic acid ester and any of their mixtures.
    [0102] In particular, aliphatic alcohol is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, isobutanol and any mixtures thereof. In particular, aliphatic alcohol is selected from methanol and ethanol and any mixtures thereof.
    [0103] Examples of suitable carbonic acid esters are n-butyl acetate or ethyl acetate and any mixtures thereof.
    [0104] In general, for the crystallization step, the reaction solvent, in particular, dimethylformide as described above, is first evaporated to a large extent, preferably under reduced pressure. Preferably at least 55% of the solvent, more preferably at least 60% of the solvent, more specifically, at least 70% of the solvent are removed. Specifically, it can be preferably, if at least 80%, more specifically, at least 90% of the solvent, such as DMF, are removed. The solvent can then be recycled to be used again in the process step (ii), if necessary, then it has been rectified previously.
    [0105] Then water and its suitable solvent, such as an ether, for example, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methylene chloride and / or tolulene, in particular, toluene are added. Also ethyl acetate and / or n-butyl acetate is suitable as a solvent. Product I is preferably obtained by crystallization directly from the concentrate, for example, from the toluene reaction mixture. Also preferably and suitable, according to the present invention, is the change of solvent, for example, to methanol or ethanol (see above) for the crystallization of the products.
    [0106] According to one embodiment, the seed crystals are added for the crystallization step.
    [0107] When using the crystallization step, especially when carrying out the process steps (iv), the formation of the unwanted symmetrical triazole (ICs-1), as described above, can be reduced to equal to or less than 10%, from greater preference, equal to or less than 8%, even more preferably, equal to or less than 5%, even more preferably, equal to or less than 2%.
    [0108] Preferably, the ratio of the isolated compound (IC-1) to the symmetrical triazole (ICs-1) is at least 20: 1, more preferably, at least 30: 1, greater preferably, 50: 1, more specifically, 70: 1. In particular, the ratio of the compound from (IC-1) to (ICs-1) is at least 30: 1.
    [0109] Other methods of additional reaction of oxirans (IB) to final products (IC) can also be carried out.
    [0110] For example, the compound epoxide ring (IB) can be cleaved by reaction with the alcohols R2OH, preferably under acidic conditions to result in compounds IX:

    [0111] The resulting compounds IX are then reacted with halogenating or sulfonating agents, such as PBr3, PCl3 mesyl chloride, tosyl chloride or thionyl chloride, to obtain compounds X in which LG 'is a group nucleophilically substitutable outlet, such as halogen, alkylsulfonyl, alkylsulfonyloxy and arylsulfonyloxy, preferably chlorine, bromine or iodine, especially preferably bromine or alkylsulfonyl. Then, compounds X are reacted with 1H-1,2,4-triazole to obtain the compounds IC, as is known in the art and / or described above:

    [0112] To obtain Formula IC compounds, in which the alcohol group is derived in an ether group to result in Formula IC-2 compounds, in which the variables are defined above, the following step can be performed: (v ) derivation of the compound of Formula (IC-1), as defined in step (iv), under basic conditions with R2-LG, where LG is a nucleophilically substitutable leaving group; to result in compounds (IC-2).
    [0113] LG represents a nucleophilically substitutable leaving group, such as halogen, alkylsulfonyl, alkylsulfonyloxy and arylsulfonyloxy, preferably chlorine, bromine or iodine, especially preferably bromine. Preferably, a base is used in step (iii) such as, for example, NaH.
    [0114] Suitable solvents, for example, are ethers, in particular cyclic ethers. Possible solvents, for example, are tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-Me-THF), diethyl ether, TBME (tert-butylmethyl ether), CPME (cyclopentylmethyl ether), DME (1 , 2-dimethoxyethane) and 1,4-dioxane. Other solvents that may be suitable, for example, are diisopropyl ether, di-n-butyl ether and / or diglyme. Often, the use of THF or 2-methyl-THF is especially suitable. In addition, it may also be suitable to use combinations of two or more different solvents, such as, for example, any combination of the solvents mentioned above or any of the ethers listed with aliphatic hydrocarbons such as n-hexane, heptane or aromatic hydrocarbons , such as toluene or xylenes.
    [0115] The person skilled in the art is familiar with the reaction in step (v) and can vary the reaction conditions in a manner similar to the known syntheses.
    [0116] In one embodiment, a Formula IC triazole compound is obtained through (iv-a) the reaction of an Formula (IB) oxirane, as defined herein; with 1H-1,2,4-triazole and an inorganic base, in which less than 1 equivalent of said base is used per 1 equivalent of the compound (IB), resulting in compounds of Formula (IC).
    [0117] To obtain compounds of Formula (IC-2), in which the alcohol group is derived (resulting in "OR2", see above), the derivation step above can be performed.
    [0118] In the definitions of the variables provided in the present, the collective terms, in general, representative of the substituents in question are used. The term "Cn-Cm" indicates the number of possible carbon atoms in each case in the substituent or in the substituent part in question.
    [0119] The term "halogen" refers to fluorine, chlorine, bromine and iodine.
    [0120] The term "C1-C6 alkyl" refers to a saturated straight or branched chain hydrocarbon group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1- methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2 methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1 - methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl , 1-ethylbutyl, 2 ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-tri-methylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Likewise, the term "C1C4 alkyl" refers to a straight or branched chain alkyl group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso- propyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl).
    [0121] The term "C3-C8 cycloalkyl" refers to monocyclic saturated hydrocarbon radicals containing 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cycloalkyl. Likewise, the term "C3-C6 cycloalkyl" refers to monocyclic saturated hydrocarbon radicals containing 3 to 6 carbon ring elements, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
    [0122] The meanings and meanings preferably described herein for the variables R1, R2, R4, X, R 'and R' 'apply to all compounds and to the precursors of the compounds and by-products in any of the process steps detailed in the present.
    [0123] R4, according to the present invention, independently, is selected from F and Cl. Specifically, the following compounds from IC.1 to IC.7 can advantageously be prepared using the process according to the present invention: - compound IC.1: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl ) phenyl] -1- (1,2,4-triazol-1-yl) propan-2-ol; - compound IC.2: 1- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1- cyclopropyl-2- (1,2,4-triazol-1-yl) ethanol; - compound IC.3: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -3-methyl- 1- (1,2,4-triazol-1-yl) butan-2-ol; - compound IC.4: 2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -1- (1,2,4-triazol-1-yl) butan-2-ol; - compound IC.5: 1- [2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methoxy-propyl] -1,2,4-triazole; - compound IC.6: 1- [2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-cyclopropyl-2-methoxy-ethyl] -1,2,4-triazole; - compound IC.7: 1- [2- [4- (4-chlorophenoxy) -2- (trifluoromethyl) phenyl] -2-methoxy-butyl] 1,2,4-triazole;
    [0124] The compounds (IC) comprise the chiral centers and, in general, are obtained in the form of racemates. The R- and S- enantiomers of the compounds can be separated and isolated in pure form with the methods known to the person skilled in the art, for example, using chiral HPLC. In addition, components I may be present in different crystal modifications, which may differ in biological activity. The compounds can be present in several crystal modifications. They are also provided by the present invention. EXAMPLES
    [0125] The following examples further illustrate the present invention and do not restrict the present invention in any way. EXAMPLES 1 TO 4
    [0126] Preparation of compound (II) with X = F, R1 = CH3 from compound (III), with X = F:
    [0127] A mixture of isopropyl chloride (32.5 g) and isopropyl bromide (232 g) is added to a stirred suspension of fresh Mg shavings (55.9 g), fresh THF (1415 g) and a small retention of the last batch (9.7 g of Mg shavings and some isopropyls of Grignard) at about 50 ° C within 1 h. The resulting suspension is stirred at about 60 ° C for an additional hour. After cooling to about 25 ° C, the remaining Mg chips were left to sediment and most of the Grignard supernatant solution (1735 g) was transferred to a solution of compound (III) (490 g) in toluene (144 g) at about 20 to 32 ° C within 45 min. The resulting solution was stirred at about 25 ° C for an additional hour and then transferred to a suspension of acetyl chloride (196 g) and copper (I) chloride (6.1 g) in toluene (737 g ) at a temperature of about Tacila (see Table below) in a tacila time min. The resulting suspension was stirred at the same temperature for an additional hour and then cautiously hydrolyzed by adding fresh water and the second and third aqueous phases of the last batch (982 g combined) at about 0 ° C. While the temperature was increased during processing, it was not allowed to exceed 25 ° C. After phase separation, the aqueous phase was discarded and the organic phase was washed with fresh water (544 g) and aqueous HCl (32%, 10 g). After phase separation, the aqueous phase was maintained for the next batch and the organic phase was washed with a mixture of aqueous NaOH (50%, 5 g) and water (15 g). After phase separation, the aqueous phase was again maintained for the next batch and the organic phase was distilled under vacuum (from 750 to 120 mbar, crankcase temperature up to 115 ° C). The resulting crude compound (II) was weighed and analyzed according to the following Table 1, in which the amount of unwanted side products observed, chlorobutyl 4-acetate, 4-bromobutyl acetate and "others" (not specified otherwise) ) is listed. It can be seen that processing under the reaction conditions of the present invention leads to a higher purity of the reaction product, that is, a higher content of the desired product (II):
    a calculated from the resulting weight and purity b% w / w of the quantitative analytical method 1 (HPLC) c% w / w of the quantitative analytical method 2 (GC) d calculated from the purity and content of the three known impurities shown in this Table and not detected
    [0128] Quantitative analytical method 1 (HPLC): - Agilent device with Agilent Zorbax Eclipse XDB-C18, 1.4 mL / min of acetonitrile / water with 0.1% 1.5% phosphoric acid, UV detection at 210 nm.
    [0129] Quantitative analytical method 2 (GC): - Agilent 6890N with Agilent CP7667, 3 mL / min H2, injection at 280 ° C, 8 min at 60 ° C, with 15 ° C / min at 280 ° C, detection (FID) at 320 ° C.
    权利要求:
    Claims (12)
    [0001]
    1. PROCESS FOR THE PREPARATION OF KETONE COMPOUNDS
    [0002]
    2. PROCESS, according to claim 1, characterized in that the Cu (I) catalyst is added in step (i).
    [0003]
    PROCESS, according to claim 2, characterized in that the Cu (I) catalyst is Cu (I) Cl.
    [0004]
    PROCESS according to any one of claims 1 to 3, characterized in that R 'is iso-propyl.
    [0005]
    PROCESS according to any one of claims 1 to 4, characterized in that Hal is Br or Cl, preferably Br.
    [0006]
    PROCESS according to any one of claims 1 to 5, characterized in that X is F.
    [0007]
    PROCESS according to any one of claims 1 to 6, characterized in that R1 is selected from CH3, CH (CH3) 2 and cyclopropyl.
    [0008]
    PROCESS according to any one of claims 1 to 7, characterized in that the temperature during the reaction with (V) is maintained in the range from -15 ° C to 5 ° C.
    [0009]
    PROCESS according to any one of claims 1 to 8, characterized in that the temperature during the reaction with (V) is maintained in the range from -10 ° C to -5 ° C.
    [0010]
    10. PROCESS FOR THE PREPARATION OF TRIAZOLE COMPOUNDS OF FORMULA (IC)
    [0011]
    11. PROCESS, according to claim 10, characterized by the reaction to form the oxirane (IB) being carried out with a trimethylsulf (ox) onide halide ((CH3) 3S + (O) Hal-) (VII), in which Hal is halogen, or methyl trimethylsulfonium sulfate of Formula (VIII) (CH3) 3S + CH3SO4-.
    [0012]
    PROCESS according to any one of claims 10 to 11, characterized in that R4 is Cl.
    类似技术:
    公开号 | 公开日 | 专利标题
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    引用文献:
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    法律状态:
    2020-04-07| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-01-19| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-02-02| B09W| Correction of the decision to grant [chapter 9.1.4 patent gazette]|Free format text: REPUBLIQUE-SE, POR INCORRECAO NO TITULO |
    2021-02-23| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 14/06/2016, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP15172535|2015-06-17|
    EP15172535.5|2015-06-17|
    PCT/EP2016/063647|WO2016202807A1|2015-06-17|2016-06-14|Process for the preparation of substituted phenyl ketones|
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