WO2019224138A1 - Verfahren zur herstellung von substituierten n-arylpyrazolen - Google Patents
Verfahren zur herstellung von substituierten n-arylpyrazolen Download PDFInfo
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- WO2019224138A1 WO2019224138A1 PCT/EP2019/062922 EP2019062922W WO2019224138A1 WO 2019224138 A1 WO2019224138 A1 WO 2019224138A1 EP 2019062922 W EP2019062922 W EP 2019062922W WO 2019224138 A1 WO2019224138 A1 WO 2019224138A1
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- 0 Cc(cc1*)cc(*)c1-[n]1nccc1 Chemical compound Cc(cc1*)cc(*)c1-[n]1nccc1 0.000 description 4
Classifications
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
Definitions
- the present invention relates to a process for the preparation of compounds of the formula (I)
- R 1 , R 2 and R 3 have the meanings described below.
- a possible process for the preparation of compounds of the formula (I) or their precursors is described, for example, in US2003 / 187233, WO2015 / 067646, WO2016 / 174052 and WO2015 / 067646.
- the preparation is carried out by diazotization with sodium nitrite in aqueous hydrochloric acid or under anhydrous conditions in acetic acid and sulfuric acid and subsequent reduction with tin (II) chloride and isolation of the hydrazine hydrochloride, which is cyclized in the subsequent step under acidic conditions.
- a disadvantage of this method is the use of stoichiometric heavy metal salts for the reduction step, as well as the isolation of a potentially toxic, and sometimes unstable hydrazine salt.
- ascorbic acid as a possible reducing agent of diazonium salts has hitherto been used for Fischer indole synthesis starting from electron-rich anilines (WO02005 / 103035, Org. Proc. Res. Dev. 2011, 15, 98) and in the synthesis of very polar aminopyrazoles (US Pat. US2002 / 0082274, RSC Adv. 2014, 4, 7019) under strongly aqueous conditions. Furthermore, Chemistry - A European Journal, 23 (39), 2017, 9407 and Molecules, 21 (918), 2016, 1 describes the use of ascorbic acid for the reduction of aryl diazonium salts under strongly aqueous conditions.
- Molecules, 21 (918), 2016, 1 also describes problems in the reaction regime and increased formation of minor components at higher aniline concentrations.
- the anilines used in the prior art have a less complex substitution pattern on the lower lipophilic aryl ring as compared to the compounds of the present invention.
- the compounds according to the invention have distinctly different polarities and thus also, for example, altered solubilities, inter alia in aqueous hydrochloric acid or under strongly aqueous conditions. These altered properties decisively influence the course of the reaction. So is a reaction under strongly aqueous conditions, as in the state of Technology described for the inventive method disadvantageous and the processes described therein can not be easily transferred to the present problem.
- V-Ary I pyrazole - 1) eri vates are of great importance as building blocks for the synthesis of new agrochemical active ingredients.
- the object of the present invention was therefore to provide a process for the preparation of compounds of general formula (I) which can be used industrially and inexpensively and circumvents the disadvantages described above. It is also desirable to obtain the specific V-Arylpy razol derivatives with high yield and high purity, so that the target compound preferably no further possibly expensive purification must be subjected.
- R 1 represents hydrogen, cyano, halogen, optionally substituted with halogen or CN or C1 to C4 alkyl optionally substituted with halogen Ci-C t -alkoxy,
- R 2 is trifluoromethylsulfonyl, trifluoromethylsulfinyl, trifluoromethylsulphanyl, halogen, optionally substituted with halogen Ci-C t alkyl or optionally substituted with halogen Ci-C alkoxy, and t
- R 3 is hydrogen, cyano, halogen, optionally substituted by halogen or CN-substituted C1-C4-alkyl or optionally substituted by halogen Ci-C4-alkoxy, wherein R 1 and R 3 are not simultaneously in a compound is hydrogen, starting from Compounds of the formula (II) in which R 1 , R 2 and R 3 have the abovementioned meaning and in which R 1 and R 3 are not simultaneously in a compound hydrogen,
- the method according to the invention has the advantage over the previously described method of dispensing with the use of stoichiometric heavy metal salts and the resulting waste.
- the hydrazines are in the form of stable intermediates and are formed only intermediately and in small amounts in the course of the reaction.
- halogen in the context of this invention preferably represents chlorine, fluorine, bromine or iodine, particularly preferably chlorine, fluorine or bromine and very particularly preferably fluorine.
- R 2 is halo-substituted Ci-C t-alkyl or halo-substituted Ci-C t alkoxy, such as difluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2 , 2,2-Trifluoroethyl, 1, 2,2,2-tetrafluoroethyl, 1-chloro-1, 2,2,2-tetrafluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 1 , 1-difluoroethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-isopropyl, nonafluoro-n-butyl, nonaflu
- R 2 is substituted by fluorine-substituted Ci-C t -alkyl or fluorine-substituted Ci-C t alkoxy.
- R 2 is perfluoro-C 1 -C 3 -alkyl (CF 3 , C 2 F 5 or C 3 F 7 (n- or iso-propyl)) or perfluoro-C 1 -C 3 -alkoxy (OCF 3 , OC 2 F 5 or OC 3 F 7 (n- or iso-propoxy)).
- R 2 is perfluoro-Ci-C3-alkyl, such as trifluoromethyl, pentafluoroethyl, heptafluoro-iso-propyl or heptafluoro-n-propyl, in particular heptafluoro-iso-propyl.
- R 1 and R 3 are each independently a substituent selected from hydrogen, CI, Br, F, C 1 -C 3 -alkyl, halogen-substituted C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or with halogen substituted Ci-C3-alkoxy.
- R 1 and R 3 are the substituents described herein, but R 1 and R 3 are not simultaneously in a compound hydrogen.
- R 1 in a compound is hydrogen
- R 3 is one of the other substituents described herein and vice versa.
- R 1 and R 3 are each independently of one another CI, Br, C 1 -C 3 -alkyl, or fluorine-substituted C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or fluorine-substituted C 1 -C 3 -alkoxy, such as CI, Br, methyl, trifluoromethyl, trifluoromethoxy or difluoromethoxy.
- R 1 and R 3 independently of one another are CI, Br or F, in particular CI or Br.
- R 1 and R 3 are the same halogen, in particular chlorine.
- At least one of the radicals R 1 , R 2 , R 3 is halogen-substituted Ci-C t -alkyl or halogen-substituted Ci-C t -alkoxy, particularly preferably fluorine-substituted Ci-C3 Alkyl or fluorine-substituted Ci-C3-alkoxy.
- R 1 is halogen or C 1 -C 3 -alkyl, in particular Br, Cl or methyl,
- R 2 is substituted by fluorine-substituted Ci-C t- alkyl or fluorine-substituted Ci-C t alkoxy, in particular heptafluoro-iso-propyl and
- R 3 is halogen, C 1 -C 3 -alkyl or fluorine-substituted C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or fluorine-substituted C 1 -C 3 -alkoxy, in particular Cl, methyl, trifluoromethyl, trifluoromethoxy or difluoromethoxy.
- alkyl is a radical of a saturated, aliphatic hydrocarbon group of 1 to 12 preferred 1 to 6 and particularly preferably 1 to 4 carbon atoms, which may be branched or unbranched.
- C 1 -C 12 -alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl , 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl.
- alkoxy either alone or in combination with other terms, such as, for example, haloalkoxy, is understood herein to mean a radical O-alkyl, the term “alkyl” having the meaning given above.
- aryl is understood according to the invention to mean an aromatic radical having 6 to 14 carbon atoms, preferably phenyl, naphthyl, anthryl or phenanthrenyl, particularly preferably phenyl.
- Particularly preferably used according to the invention are processes in which a combination of the meanings and ranges listed above as being particularly preferred is present.
- Very particularly preferably used according to the invention are processes in which a combination of the meanings and ranges listed above as being very particularly preferred is present.
- R is (Ci-Ce) alkyl, preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso Butyl, tert-butyl, n-pentyl or iso-pentyl
- the invention preferably between 0.9 and 2.0 equivalents, particularly preferably between 1.0 and 1.5 equivalents, very particularly preferably between 1.0 and 1.2 equivalents, based on the total molar amount of the compounds of the formula ( II), the compounds of the formula RNO 2 or M (NC> 2 ) n used.
- the use of larger surpluses is chemically possible, it does not make economic sense.
- the nitrites are thereby preferably in pure form or, in the case of M (NC> 2 ) n , as pure form or as aqueous solution in concentrations of 10-80% by weight, more preferably in pure form or as aqueous solution in concentrations of 20-60 % By weight and very particularly preferably in pure form or used as aqueous solution in concentrations of 35-50% by weight.
- Suitable nitrites RNO 2 or M (NC> 2 ) n are z.
- alkali or Erdalkalinitrite or ammonium nitrite and (Ci-C6) -alkyl nitrites Preference is given to F1NO 2 , NaNCF, KNO 2 , MgtNCEh, Ca (NC> 2) 2, Ba (NC> 2) 2, n-butylnitrite, tert-butylnitrite, n-pentylnitrite or isopentylnitrite, particular preference is given to F1NO 2 , NaNCF, KNO 2 , tert-butyl nitrite or isopentyl nitrite, most preferably NaNCF.
- the nitrites may be used alone or in combination of two or more nitrites.
- the acid is preferably used according to the invention in amounts, based on the total amount of substance used of the compounds of the general formula (II), between 1.0 and 20.0 equivalents, more preferably between 3.0 and 10.0 equivalents, very particularly preferably between 2 , 0 and 7.0 equivalents used.
- the acid is used according to the invention preferably in pure form or as an aqueous solution in concentrations of 10-99 wt.%, Particularly preferably in pure form or as an aqueous Solution in concentrations of 20-80 wt.%, Most preferably in pure form or as an aqueous solution in concentrations of 25-60 wt.%.
- Suitable acids are preferably selected according to the invention from mineral acids, sulfonic acids and carboxylic acids, the carboxylic acids having a pKa of ⁇ 2.
- mineral acids includes all noncarbonated, inorganic acids, such as, for example, HF, HCl, HBr, HI, H 2 SO 4, HNO 3 , and H 3 PO 4 .
- Suitable mineral acids are more preferably selected from HI, HBr, HCl, H2SO4 and H3PO4, most preferably from H2SO4 and H3PO4 and particularly preferred is H2SO4.
- sulfonic acids comprises the optionally substituted aryl and alkylsulfonic acids which are generally known to the person skilled in the art, for example methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
- Suitable sulfonic acids are more preferably selected from methanesulfonic acid, trifluoromethanesulfonic acid and para-toluenesulfonic acid, very particularly preferably from methanesulfonic acid and trifluoromethanesulfonic acid and particularly preferred is methanesulfonic acid.
- carboxylic acids encompasses all carbon-containing acids which are generally known to the person skilled in the art and contain at least one carboxy group (-COOH), for example optionally substituted alkyl and arylcarboxylic acids and optionally substituted alkyl- and aryl-dicarboxylic acids which have a pKa value of ⁇ 2, preferably of ⁇ 1.
- Suitable carboxylic acids are more preferably selected from trifluoroacetic acid, dichloroacetic acid and trichloroacetic acid, most preferably trifluoroacetic acid.
- the acids can be used alone or in combination of two or more acids.
- Step (1) is preferably carried out in a suitable solvent.
- suitable solvents are, for example: carboxylic acids (eg acetic acid, -P -propanoic acid, n-butanoic acid), esters (such as eg ethyl acetate, propyl (n and iso) acetate, butyl acetate), ethers (eg.
- Tetrahydrofuran (THF), 2-methyl-THF, diglyme, 1,2-dimethoxyethane (DME), 1,4-dioxane), nitriles (eg acetonitrile, propionitrile), amide solvents (eg / V, / V-) Dimethylformamide (DMF), / V, / V-dimethylacetamide (DMAC), V-methylpyrrolidone (NMP)), alcohols (eg methanol, ethanol, propanol (n- and iso)) and dipolar aprotic solvents (eg DMSO) or mixtures of these solvents mentioned.
- amide solvents eg / V, / V-
- DMF Dimethylformamide
- DMAC / V, / V-dimethylacetamide
- NMP V-methylpyrrolidone
- alcohols eg methanol, ethanol, propanol (n- and iso)
- Preferred solvents are acetonitrile, acetic acid, ethyl acetate, THE, DMAC, DME, diglyme or 1,4-dioxane. Very particular preference is given to acetic acid and acetonitrile or mixtures of acetonitrile and acetic acid.
- the diazotization (step (I)) is preferably carried out at an ambient temperature in the range of -10 ° C to 80 ° C, more preferably in the range of 0 ° C to 60 ° C, most preferably in the range of -5 ° C to 40 ° C performed.
- the diazotization is carried out in the range of atmospheric pressure (1013 hPa), z. In the range from 300 hPa to 5000 hPa or from 500 hPa to 2000 hPa, preferably as in the range of 1013 hPa ⁇ 200 hPa.
- the reaction time of the diazotization is preferably in the range of the metering time of the nitrite.
- the implementation is instantaneous. The skilled person can estimate the dosing time from his experience without any problems. However, preference is given to at least half an hour, more preferably the metering time is in the range from 0.5 h to 3 h, very particularly preferably from 0.25 to 1.5 h.
- a diazonium salt of the formula (III) is formed,
- R 1 , R 2 , R 3 are as defined above, wherein R 1 and R 3 are not simultaneously in a compound hydrogen, and X n according to the invention for a person skilled in the well-known corresponding base of the acids according to the invention from step (1)
- X n for a person skilled in the well-known corresponding base of the acids according to the invention from step (1)
- F 3 CSO 3 , MeSCE, HSO 4 , SO 4 2 and H 2 PO 4 and n is 1 or 2.
- a reduction with ascorbic acid is carried out after step (1) in a further step (2).
- Ascorbic acid is preferably used in amounts of 0.9 to 2.0 equivalents, based on the total amount of substance used of the compound of formula (II), more preferably between 1.0 and 1.5 equivalents, most preferably between 1, 0 and 1.2 equivalents.
- Ascorbic acid can be used as a solid or as an aqueous solution in concentrations of 5-40% by weight, preferably as a solid or aqueous solution in concentrations of 10-30% by weight, very particularly preferably as a solid or aqueous solution in concentrations of 15% by weight. 25% by weight.
- Ascorbic acid can exist in four stereoisomeric forms. Both the use of one of the four pure isomeric ascorbic acids and mixtures of isomers is the subject of the process according to the invention.
- the addition of the ascorbic acid to the reaction mixture from step (1) may be particularly preferred according to the invention in one portion or over a period of 0.5-6 hours, more preferably in one portion or over a period of 0.25-4 hours in one portion or over a period of 0.5-3 hours. Although a longer dosing time is technically possible, it does not make economic sense.
- the reduction is carried out according to the invention preferably without further dilution in the same solvent in which step (1) has already taken place.
- the reduction can be carried out according to the invention preferably by adding ascorbic acid to a solution of the compounds of the general formula (III) in one of the solvents mentioned above under step (1) or by inverse metering.
- the reduction reaction with ascorbic acid is preferably carried out at an ambient temperature in the range of -10 ° C to 80 ° C, more preferably in the range of 0 ° C to 60 ° C and most preferably in the range of -5 ° C to 40 ° C.
- the reaction in the range of atmospheric pressure (1013 hPa) is carried out, for. In the range from 300 hPa to 5000 hPa or from 500 hPa to 2000 hPa, preferably as in the range of 1013 hPa ⁇ 200 hPa.
- reaction time of the reduction is preferably in the range of at least 5 minutes to 5 hours, more preferably at least 15 minutes to 3 hours, and most preferably at least 30 minutes to 2 hours.
- a base is added after step (2) in a further step (2-a), whereby compounds of the formula (V) are precipitated,
- R 1 , R 2 , R 3 are as defined above, wherein R 1 and R 3 are not simultaneously in a
- This process variant is particularly advantageous, since these compounds have a particularly favorable solubility behavior in conventional solvents for further processing, and these can thus be obtained in particularly high purities and very good yields.
- Suitable bases are, for example, carbonates (such. As (NH ⁇ t CCb, L1 2 CO 3, NazCCL, K 2 CO 3, CaCCb, MgCCL), bicarbonates (such as, for example, NH 4 HCO 3, L1HCO 3, NaHCCb , KHCO 3 ), carboxylates (KOAc, NaOAc, LiOAc, KOOCH, NaOOCH, LiOOCH) or hydroxides (such as, for example, LiOH, NaOH, KOH).
- carbonates such. As (NH ⁇ t CCb, L1 2 CO 3, NazCCL, K 2 CO 3, CaCCb, MgCCL
- bicarbonates such as, for example, NH 4 HCO 3, L1HCO 3, NaHCCb , KHCO 3
- carboxylates such as, for example, NaOAc, LiOAc, KOOCH, NaOOCH, LiOOCH
- hydroxides such as, for example, LiOH, NaOH, KOH
- Hydrogen carbonates in particular NaHCCL or KHCO 3 , carbonates, in particular Na 2, are preferred according to the invention CC> 3 or K 2 CO 3 or hydroxides, in particular NaOH or KOH, particularly preferably Nal ICO ,, Na 2 C0 3 or NaOH and very particularly preferably Nal ICO 3 or NaOH, or mixtures of the abovementioned bases.
- the base is preferably used in amounts between 1.0 and 5.0 equivalents (monovalent bases) or between 0.5 and 2.5 equivalents (divalent bases), based on the total amount of substance used of the compounds of the formula (II), used, more preferably between 1.2 and 3.0 equivalents (monovalent bases) or between 0.6 and 1.5 equivalents (divalent bases), very particularly preferably between 1.1 and 2.5 equivalents (monovalent bases) or between 0.55 and 1.75 equivalents (bivalent bases).
- step (2-a) occurs with steps (1) and (2) in a one-pot reaction
- the amounts of base must be adjusted so that the acids present initially neutralize from these steps become. This results in the following amounts of base:
- the base is then preferably used in amounts between 5 and 200 equivalents (monovalent bases) and between 2.5 and 100 equivalents (divalent bases), based on the total Substance of the compounds of formula (II) used, more preferably between 10 and 100 equivalents (monovalent bases) and between 5 and 50 equivalents (divalent bases), most preferably between 20 and 60 equivalents (monovalent bases) and between 10 and 30 equivalents (bivalent bases).
- the base is preferably used in pure form or as an aqueous solution in concentrations of 1-70% by weight, particularly preferably as aqueous solution in concentrations of 5-50% by weight, very particularly preferably as aqueous solution in concentrations of 5-30% by weight. used.
- the base is further added to a solution of the mixture of step 2, containing the products (IV a) and (IVb), in a suitable organic solvent.
- a water-soluble organic solvent from the group of ethers (such as tetrahydrofuran (THF), 2-methyl-THF, diglyme, 1,2-dimethoxyethane (DME), 1,4-dioxane), nitriles (such as Acetonitrile, propionitrile), amide solvents (such as DMF, DMAC, NMP), alcohols (such as methanol, ethanol, propanol (n- and iso)), ketones (e.g.
- ethers such as tetrahydrofuran (THF), 2-methyl-THF, diglyme, 1,2-dimethoxyethane (DME), 1,4-dioxane
- nitriles such as Acetonitrile, propionitrile
- amide solvents such as DMF, DMAC, NMP
- Acetone, ethyl methyl ketone) and dipolar aprotic solvents such as DMSO or mixtures of these solvents.
- Particularly preferred are methanol, iso-propanol, acetone, THF, DMAC and acetonitrile.
- Most preferred is acetone.
- the addition of the base is carried out according to the invention preferably under pH control, wherein a pH range between 1 and 10 is passed through.
- the reaction with base is preferably carried out at an ambient temperature in the range of 0 ° C to 80 ° C, more preferably in the range of 15 ° C to 60 ° C and most preferably in the range of 10 ° C to 35 ° C.
- the reaction in the range of atmospheric pressure (1013 hPa) is carried out, for. In the range from 300 hPa to 5000 hPa or from 500 hPa to 2000 hPa, preferably as in the range of 1013 hPa ⁇ 200 hPa.
- the reaction time of the salt formation to compounds of the general formula (V) is preferably in the range from 0.5 h to 48 h, particularly preferably at least 3 h to 24 h and very particularly preferably from 2 h to 12 h.
- the compounds of the formula (V) are preferably isolated by filtration and subsequent washing with water and, if appropriate, finally with an organic, nonpolar aprotic solvent which is inert under the specific reaction conditions.
- Suitable organic, non-polar aprotic solvents are: halogenated hydrocarbons (for example chlorohydrocarbons, such as tetrachloroethane, dichloropropane, Methylene chloride, 1,2-dichloroethane, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene, pentachloroethane), halogenated, aromatic hydrocarbons (eg difluorobenzene, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene, trichlorobenzene), aliphatic, cycloaliphatic or aromatic hydrocarbons (eg pentane, Hexane, heptane, octane, nonane and technical hydrocarbons, cyclohexane, methylcyclohexane, petroleum ether, ligroin, benzene, tolu
- Dichloromethane, chlorobenzene, toluene, xylene, mesitylene, heptane, methylcyclohexane, ethyl acetate, methyl tert-butyl ether or methyl cyclopentyl ether are particularly preferably used, very particular preference is heptane, methyl tert-butyl ether, xylene or mesitylene.
- the solvents may be used alone or in combination of two or more.
- step (2) or step (2-a) in a further step (2-b) at least one compound of the formula R 5 -OH is added, whereby, in the presence of at least one acid selected from Mineral acids or sulfonic acids, compounds of formula (VI) arise,
- R 1 , R 2 , R 3 are as defined above, wherein R 1 and R 3 are not simultaneously in a compound is hydrogen, and R 5 is Ci-C t -alkyl.
- Step (2-b) is carried out in the presence of at least one acid selected from mineral acids or sulfonic acids.
- at least one acid selected from mineral acids or sulfonic acids In the event that from step (1) already exists a suitable acid and this was not removed during the process by purification or isolation of the intermediates, no further acid must be added. Otherwise, the acid is newly added in step (2-b).
- Suitable acids are selected according to the invention from mineral acids and sulfonic acids.
- mineral acids includes all noncarbonated, inorganic acids, such as, for example, HF, HCl, HBr, HI, H 2 SO 4, HNO 3 , and H 3 PO 4 .
- Suitable mineral acids are particularly preferably selected from HI, HBr, HCl, H2SO4 and H3PO4, very particularly preferably from H2SO4, HBr and HCl and particularly preferred is H2SO4.
- the term sulfonic acids comprises the optionally substituted aryl and alkylsulfonic acids which are generally known to the person skilled in the art, for example methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
- Suitable sulfonic acids are more preferably selected from methanesulfonic acid, trifluoromethanesulfonic acid and para-toluenesulfonic acid, very particularly preferably from methanesulfonic acid and trifluoromethanesulfonic acid and particularly preferred is methanesulfonic acid.
- the suitable acids are selected from HCl, H 2 SO 4 , H 3 PO 4 , methanesulfonic acid, trifluoromethanesulfonic acid or para-toluenesulfonic acid, very particularly preferably from H 2 SO 4 , HCl, methanesulfonic acid or trifluoromethanesulfonic acid, in particular preferably from H 2 SO 4 or methanesulfonic acid.
- the acids can be used alone or in combination of two or more acids.
- the acid can be used according to the invention preferably as a pure substance or as a solution in a suitable, under the reaction conditions inert organic solvent, in particular the previously preferred for the reaction solvent, preferably in a concentration of> 30 wt.%, More preferably in a concentration of > 60% by weight.
- the acid is particularly preferably used as a pure substance and in mineral acids in their commercially available, concentrated Lorm without further dilution.
- the acid is added in step (2-b) preferably in amounts, based on the total amount of substance used of the compounds of the general formula (II), between 1.0 and 6.0 equivalents, more preferably 1.5 to 4.0 Equivalents, most preferably used 1.2 to 3.0 equivalents.
- R 5 in the case of compounds of the formula (VI) is (C 1 -C 4) -alkyl, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl or tert-butyl, preferably methyl or ethyl ,
- the alcohol R 5 -OH is preferably used simultaneously as solvent and reagent.
- the use of stoichiometric amounts of the alcohol R 5 -OH, based on the total amount used of compounds of the formula (II) in combination with inert solvents under the reaction conditions, such as toluene, xylene or chlorobenzene is also possible according to the invention, but is less preferred.
- Step (2-b) is preferably carried out at an ambient temperature in the range of 0 ° C to 150 ° C, more preferably in the range of 10 ° C to 100 ° C and most preferably in the range of 30 ° C to 90 ° C.
- the reaction in the range of atmospheric pressure (1013 hPa) is carried out, for. In the range from 300 hPa to 5000 hPa or from 500 hPa to 2000 hPa, preferably as in the range of 1013 hPa ⁇ 200 hPa.
- reaction time of step (2-b) is preferably in the range of 0.5 hours to 12 hours, more preferably from 3 hours to 8 hours, and most preferably from 2 hours to 7 hours.
- Reaction step (2-b) may follow step (2) or step (2-a).
- the process according to the invention comprises, in a further step (3), the cyclization of the compounds obtained from step (2), (2-a) or (2-b) with 1,1,3,3-tetra (C 1 -C 4 ) alkoxypropanes in a polar solvent and in the presence of at least one acid selected from mineral acids, sulfonic acids or carboxylic acids, wherein the carboxylic acids have a pKa value ⁇ 2.
- the l, l, 3,3-tetra (Ci-C 4 ) alkoxypropanes can be used alone or in combination of two or more l, l, 3,3-tetra (Ci-C 4 ) alkoxypropanes.
- the l, l, 3,3-tetra (Ci-C 4 ) alkoxypropanes are preferably in amounts, based on the total amount of substance used of compounds of formula (II), from 0.7 to 2.0 equivalents, particularly preferably from 0 , 9 to 1.5 equivalents, and most preferably from 0.8 to 1.1 equivalents.
- the use of larger surpluses does not make economic sense.
- the l, l, 3,3-tetra (Ci-C 4 ) alkoxypropane compounds can be added or metered in one portion.
- the 1,1,3,3-tetra (C 1 -C 4 ) alkoxypropanes are preferably added in one portion.
- Suitable polar solvents for step (3) are the conventional polar solvents known to the person skilled in the art, for example water, aqueous mineral acids, in particular hydrochloric acid or sulfuric acid, carboxylic acids, in particular acetic acid, n-propanoic acid or n-butanoic acid, ethers, especially tetrahydrofuran (THF), 2-methyl-THF, diglyme, 1,2-dimethoxyethane (DME) or 1,4-dioxane, nitriles, in particular acetonitrile or propionitrile, amide solvent, in particular N, N-dimethylformamide (DMF), V, / V-dimethylacetamide (DMAC) or / V-methylpyrrolidone (NMP), alcohols, in particular methanol, ethanol or propanol (n- and iso), and dipolar aprotic solvents (eg DMSO).
- water aqueous mineral acids, in particular hydrochloric
- aqueous hydrochloric acid Preference is given to using aqueous hydrochloric acid, aqueous sulfuric acid, acetic acid, methanol or ethanol, and it is particularly preferable to use methanol.
- the solvents may be used singly or in admixture of two or more.
- the compound R 5 -OH from step (2-b) serves as solvent for step (2-b) and step (3).
- Step (3) is carried out in the presence of at least one acid selected from mineral acids, sulfonic acids or carboxylic acids, wherein the carboxylic acids have a pKa value ⁇ 2.
- step (3) is carried out in an aqueous mineral acid according to the invention or a carboxylic acid with pKs ⁇ 2 as solvent.
- Suitable acids are selected according to the invention from mineral acids, sulfonic acids and carboxylic acids, the carboxylic acids having a pKa value ⁇ 2.
- mineral acids includes all noncarbonated, inorganic acids, such as, for example, HF, HCl, HBr, HI, H 2 SO 4, HNO 3 , and H 3 PO 4 .
- Suitable mineral acids are more preferably selected from HI, HBr, HCl, H 2 SO 4 and H 3 PO 4 , very particularly preferably from H 2 SO 4 , HBr and HCl and particularly preferred is H 2 SO 4 .
- sulfonic acids comprises the optionally substituted aryl and alkylsulfonic acids which are generally known to the person skilled in the art, for example methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
- Suitable sulfonic acids are more preferably selected from methanesulfonic acid, trifluoromethanesulfonic acid and para-toluenesulfonic acid, very particularly preferably from methanesulfonic acid and trifluoromethanesulfonic acid and particularly preferred is methanesulfonic acid.
- carboxylic acids encompasses all carbon-containing acids which are generally known to the person skilled in the art and contain at least one carboxy group (-COOH), for example optionally substituted alkyl and arylcarboxylic acids and optionally substituted alkyl and aryl-dicarboxylic acids having a pKa value of ⁇ 2, preferably of ⁇ 1.
- Suitable carboxylic acids are more preferably selected from dichloroacetic acid, trichloroacetic acid and trifluoroacetic acid, most preferably trifluoroacetic acid.
- the suitable acids selected from HCl, H 2 SO 4 , H 3 PO 4 , methanesulfonic acid, trifluoromethanesulfonic acid, para-toluenesulfonic acid, trichloroacetic acid, dichloroacetic acid and trifluoroacetic acid are very particular preferably from H 2 SO 4 , HCl, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid, more preferably from H 2 SO 4 or methanesulfonic acid.
- the acids can be used alone or in combination of two or more acids.
- the acid can be used according to the invention preferably as a pure substance or as a solution in a suitable, under the reaction conditions inert organic solvent, in particular the previously preferred for the reaction solvent, preferably in a concentration of> 30 wt.%, More preferably in a concentration of > 60% by weight.
- the acid is particularly preferably used as pure substance and in mineral acids in their commercially available, concentrated form without further dilution.
- the acid is added in step (3) preferably in amounts, based on the total amount of substance used of the compounds of general formula (II), between 1.0 and 6.0 equivalents, more preferably 1.5 to 4.0 equivalents, most preferably used 1.2 to 3.0 equivalents.
- the ring closure reaction with 1,1,3,3-tetra (C 1 -C 4 ) alkoxypropane compounds is preferably still at an ambient temperature in the range of 0 ° C to 100 ° C, more preferably in the range of 20 ° C to 90 ° C more preferably in the range of 40 ° C to 80 ° C.
- the reaction in the range of atmospheric pressure (1013 hPa) is carried out, for. In the range from 300 hPa to 5000 hPa or from 500 hPa to 2000 hPa, preferably as in the range of 1013 hPa ⁇ 200 hPa.
- the reaction time of the ring closure reaction is preferably in the range from 0.05 h to 30 h, particularly preferably in the range from 0.5 h to 20 h, very particularly preferably in the range from 2 h to 15 h, in particular in the range from 4 h to 8 H.
- the workup and isolation of the compounds (I) can, after complete reaction, take place, for.
- the residue can furthermore be subjected to a vacuum distillation at 0.05-1 mbar with a canned column and crystallization in a solvent generally known to the person skilled in the art.
- the process according to the invention may comprise or consist of the following combinations of steps (1), (2), (2-a), (2-b) and (3):
- Step (1) Step (2), Step (2-a), Step (2-b) and Step (3).
- this comprises the steps (1), (2), (2-a) and (3) or consists of these steps.
- this comprises the steps (1), (2), (2-b) and (3) or consists of these steps.
- the process according to the invention particularly preferably comprises the steps (1), (2), (2-a), (2-b) and (3) or consists of these steps.
- steps (1) and (2) are carried out together in a one-pot reaction.
- the diazonium salt (III) resulting from step (1) from compound (II) is preferably not isolated or purified as a "one-pot" reaction.
- Step (2-a) can be carried out according to the invention either after isolation and optionally purification of the substance mixture from step (2) or steps (1), (2) and (2-a) take place together in a one-pot reaction.
- step (2-a) is carried out after isolation and optionally purification of the substance mixture from step (2).
- the diazonium salt (III) resulting from step (1) from compound (II) and the product mixture resulting from step (2) are not isolated or purified.
- steps (2-b) and (3) are carried out together in a one-pot reaction.
- the compound (VI) formed after step (2-b) is not isolated or purified.
- the inventive method is characterized in that after step (2) or step (2-a) in a further step (2-b), at least one compound of formula R 5 -OH is added, whereby, in the presence at least one acid selected from mineral acids or sulfonic acids, compounds of the formula (VI) are formed,
- R 1 , R 2 , R 3 are defined according to claim 1, wherein R 1 and R 3 are not simultaneously in a compound hydrogen and R 5 is Ci-C t -alkyl and also the steps (2-b) and (3) are carried out together in a one-pot reaction whereby the compound (VI) resulting from step (2-b) is not isolated or purified.
- neither the compound (VI) formed after step (2-b) is isolated or purified, nor is there any essential removal and / or replacement of solvent.
- steps (1) and (2) are carried out as a "one-pot” reaction and also steps (2-b) and (3) as a "one-pot” reaction.
- steps (1) and (2) are carried out as a "one-pot” reaction and also steps (2-b) and (3) as a "one-pot” reaction.
- step (2) isolation and, if appropriate, purification of the product mixture from step (2) and / or the compounds of the formula (V) according to step (2-a) are preferably carried out before their further reaction.
- reaction volumes in the form of solids, liquids or suspensions e.g. In the form of solid, dissolved or suspended reducing agents, or solvents (the same solvent as in the first step or another solvent) are added, however, the goal is a reaction sequence with no essential / no replacement of solvent or active removal of solvent.
- reaction sequence be telescoped reactions in one or more vessels, preferably a vessel.
- purifying in the sense of the present invention refers to the enrichment of a substance (and thus depletion of other substances) to a purity of at least 20% by weight (percent by weight of a substance based on the measured total mass are determined chromatographically (eg HPFC or gas chromatographic or gravimetric)), preferably at least 50% by weight, even more preferably at least 75% by weight, eg. B. 90 wt.%, 98 wt.% Or greater 99 wt.%.
- the compound R 5 -OH from step (2-b) serves as a solvent for step (2-b) and step (3). Particular preference is given to using the product mixture obtained from step 2 or the compounds of the formula (V) dissolved in R 5 -OH, where R 5 is as defined above.
- Scheme 1 gives a schematic overall representation of the method according to the invention with all mandatory and optional steps. Reaction conditions and reactants are selected according to the inventive and preferred embodiments described above. All variables in formulas (I), (II), (III), (IVa), (IVb), (V) and (VI) are defined as described above.
- R 6 is, independently of one another, (C 1 -C 4 -alkyl, preferably methyl or ethyl.
- a preferred embodiment of the process according to the invention is the following: The compounds of the formula (II) are initially charged in an organic solvent and after addition of an acid according to the invention, for. As sulfuric acid, with sodium nitrite, z. B.
- the isolated mixture containing the compounds (IVa) and (IVb) is subsequently dissolved in an organic solvent, e.g. Methanol or ethanol, more preferably methanol with the addition of a strong acid, eg. For example, hydrochloric acid, sulfuric acid or methanesulfonic acid, particularly preferably sulfuric acid, with compounds of general formula (VII), z. B. 1, 1,3,3-tetramethoxypropane, added.
- a strong acid eg.
- hydrochloric acid, sulfuric acid or methanesulfonic acid particularly preferably sulfuric acid
- z. B 1, 1,3,3-tetramethoxypropane
- the reaction mixture is then incubated with good stirring in a temperature range from 20 ° C to 100 ° C, more preferably in a temperature range from 40 ° C to 80 ° C for a period of 2 to 15 hours to complete conversion.
- Step (3) The resulting compounds of formula (I) can then be isolated and purified by the
- the compounds of formula (II) are initially charged in acetic acid and after addition of concentrated or aqueous sulfuric acid with aqueous sodium nitrite at 0 ° C to 60 ° C for 0.5 h to 3 h.
- ascorbic acid is added to the reaction mixture as a reducing agent, e.g. B. as a solid or aqueous solution was added.
- the isolated mixture containing the compounds (IVa) and / or (IVb) is then added in methanol after addition of concentrated sulfuric acid with compounds of general formula (VII), for example 1,1,3,3-tetramethoxypropane.
- the reaction mixture is preferably subsequently stirred with good stirring in a temperature range from 20.degree. C. to 100.degree. C., more preferably in a temperature range from 40.degree. C. to 80.degree. C. for a period of 2 to 15 hours until complete conversion (HPLC a ) incubated. (Step 3)).
- the resulting compounds of formula (I) can then be isolated and purified by the methods described above.
- the compounds of the formula (I) are prepared via the steps (1), (2), (2-a) and (3) or (1), (2), (2) a), (2-b) and (3).
- the isolated mixture comprising the compounds of general formula (IVa) and / or (IVb) after its preparation according to the invention, as described above for step (1) and (2), as a solution in an organic solvent, e.g. Acetone, with an aqueous solution of a base, e.g. Sodium hydroxide or sodium bicarbonate, added.
- an organic solvent e.g. Acetone
- a base e.g. Sodium hydroxide or sodium bicarbonate
- the reaction mixture is incubated with good stirring in a temperature range of 10 ° C to 35 ° C for a period of 3 to 12 hours.
- the reaction mixture is incubated with good stirring in a temperature range of 10 ° C to 35 ° C for a period of 3 to 12 hours.
- the isolation of the compounds of general formula (V) may e.g. by filtration, preferably with a subsequent washing with water and optionally followed by washing with an organic solvent.
- step (3) can be used directly in step (3) without further work-up.
- compounds of formula (V) according to step (2-b) of the process according to the invention can be converted into compounds of general formula (VI). Preferred embodiments of the step (2-b) will be described below.
- the compounds of the formula (I) are prepared via steps (1), (2-b) and (3).
- the mixture of substances containing the compounds of the general formula (IVa) and / or (IVb) in an organic solvent of the formula R 5 -OH, z As methanol, submitted and mixed with concentrated sulfuric acid.
- the reaction mixture is incubated with good stirring in a temperature range of 30 ° C to 90 ° C for a period of 1 to 8 hours.
- the intermediates of the general formula (VI) thus obtained can be used directly in step (3) without further workup.
- compounds of formula (VI) may be isolated and further characterized by suitable workup steps well known to those skilled in the art and used subsequently in step (3).
- the compounds of the formula (I) are prepared via steps (1), (2) and (3), and optionally (2-b) in a one-pot reaction.
- one-pot reaction is understood here to mean that the conversion of a compound of the formula (II) via steps (1), (2) and (3), and optionally (2-b) into a compound of the formula (I) meets at least one of the following conditions:
- step (1) From the solvent of step (1), only a small proportion of the solvent is removed before the start of step (2) or before the start of step (2-b) or (3), preferably less than 50% by volume (percent by volume) to the volume of the solvent used), preferably less than 30% by volume, more preferably less than 10% by volume, even more preferably not more than 5% by volume of the solvent (for example by evaporation, for example at a reaction temperature from around 40 ° C, or actively removing, for example, through Distillation and / or reduced pressure based on 1013 hPa), preferably no solvent is active by the solvent exchange between step (1) and step (2), between step (2), optionally step (2-b) and (3) and if present between step (2) and (2-b) (e.g., by distillation and / or reduced pressure relative to 1013 hPa);
- reaction volumes in the form of solids, liquids or suspensions e.g. In the form of solid, dissolved or suspended reducing agents, or solvents (the same solvent as used before step (1) or another solvent) are added, but the aim is a reaction sequence without essential / no exchange of solvent as in step (1 ) or active solvent removal as used before step (1).
- neither the diazonium salt (III) resulting from step (1) from compound (II) nor compounds of the formula (IVa), (IVb), (VI) or any compounds of the formula (VIII) which are formed are preferred. during the reaction sequence leading to compound (I) isolated or purified.
- purifying in the sense of the present invention refers to the enrichment of a substance (and thus depletion of other substances) to a purity of at least 20% by weight (percent by weight of a substance based on the measured total mass be determined chromatographically (eg HPLC or gas chromatographic or gravimetric)), preferably at least 50 wt.%, even more preferably at least 75 wt.%, eg. B. 90 wt.%, 98 wt.% Or greater 99 wt.%.
- chromatographically eg HPLC or gas chromatographic or gravimetric
- the present invention also relates to the intermediate compounds of the formulas (IV a), (IVb), (V) and (VI).
- the invention relates to compounds of the formula (V)
- Another object of the invention are compounds of formula (VI)
- R 1 and R 3 are as defined above, wherein R 1 and R 3 are not simultaneously in a compound hydrogen, R 2 is halogen-substituted Ci-C t -alkyl or halogen-substituted Ci-C t alkoxy and R 5 is C-C t -alkyl, in particular methyl or ethyl.
- Another object of the invention are compounds of the formula (IV a) and (IVb) wherein R 1 and R 3 are as defined above, wherein R 1 and R 3 are not simultaneously in a compound is hydrogen and R 2 is halogen-substituted Ci-C t -alkyl or halogen-substituted Ci-C 4 alkoxy stands.
- NMR data of the examples are listed in classical form (d values, multiplet splitting, number of H atoms).
- Step 1 and 2 Preparation of a product mixture containing N-arylhydrazino-2-oxoacetic acids (IVa)
- the mixture was warmed to room temperature over 1.5 h and the reaction mixture was washed with 200 ml of n-heptane. After addition of 500 ml of water, the product mixture was extracted with 500 ml of tert-butyl methyl ether, the organic phase washed with 20 wt.% NaCl solution and the crude product after removal of the solvent under reduced pressure directly used in the next stage.
- Step 2-a Preparation of sodium V-aryl hydrazino-2-oxoacetates (V)
- Example 3-1) 1- [2,6-dichloro-4- (1,1,2,3,3,3-heptafluoropropan-2-yl) -phenyl] -1H-pyrazole (from precursor containing compounds of the general Formula (IVa) and / or (IVb) from Step 2) (1-1)
- Example 4-1) 1- [2,6-dichloro-4- (1,1,2,3,3,3-heptafluoropropan-2-yl) phenyl] -1H-pyrazole (from precursor containing compounds of the general Formula (IVa) and / or (IVb) from Step 2) (1-1)
- Example 4-2) 1- [2,6-dichloro-4- (1,1,2,3,3,3-heptafluoropropan-2-yl) phenyl] -1H-pyrazole (from precursor of general formula ( II): One-Pot Procedure with Step 1, Step 2 and Step 3) (1-1)
- N-arylpyrazoles of the general formula (I) could be prepared: 1- [2-bromo-4- (1, 1, 1, 2,3,3,3-heptafhioropropane-2 -yl) -6- (trifluoromethoxy) phenyl] -1H-pyrazole (1-2)
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Abstract
Description
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CN201980034636.9A CN112204013A (zh) | 2018-05-24 | 2019-05-20 | 制备取代的n-芳基吡唑的方法 |
US17/058,035 US20210276958A1 (en) | 2018-05-24 | 2019-05-20 | Method for producing substituted n-aryl pyrazoles |
EP19727945.8A EP3802496A1 (de) | 2018-05-24 | 2019-05-20 | Verfahren zur herstellung von substituierten n-arylpyrazolen |
BR112020022863-0A BR112020022863A2 (pt) | 2018-05-24 | 2019-05-20 | processo para preparar n-arilpirazóis substituídos |
CA3101062A CA3101062A1 (en) | 2018-05-24 | 2019-05-20 | Method for producing substituted n-aryl pyrazoles |
MX2020012524A MX2020012524A (es) | 2018-05-24 | 2019-05-20 | Proceso para la preparacion de n-arilpirazoles sustituidos. |
JP2020564870A JP2021524461A (ja) | 2018-05-24 | 2019-05-20 | 置換n−アリールピラゾールの製造方法 |
KR1020207033630A KR20210014633A (ko) | 2018-05-24 | 2019-05-20 | 치환된 n-아릴피라졸의 제조 방법 |
IL278863A IL278863A (en) | 2018-05-24 | 2020-11-19 | A method for the production of N-aryl pyrazoles |
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- 2019-05-20 US US17/058,035 patent/US20210276958A1/en not_active Abandoned
- 2019-05-20 KR KR1020207033630A patent/KR20210014633A/ko unknown
- 2019-05-20 CN CN201980034636.9A patent/CN112204013A/zh active Pending
- 2019-05-20 CA CA3101062A patent/CA3101062A1/en active Pending
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- 2019-05-20 BR BR112020022863-0A patent/BR112020022863A2/pt active Search and Examination
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IL278863A (en) | 2021-01-31 |
MX2020012524A (es) | 2021-02-16 |
TW202012373A (zh) | 2020-04-01 |
JP2021524461A (ja) | 2021-09-13 |
BR112020022863A2 (pt) | 2021-02-23 |
CN112204013A (zh) | 2021-01-08 |
KR20210014633A (ko) | 2021-02-09 |
US20210276958A1 (en) | 2021-09-09 |
CA3101062A1 (en) | 2019-11-28 |
EP3802496A1 (de) | 2021-04-14 |
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