WO2015110493A1 - Method for preparing 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole-4-carbaldehydes and 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole-4-carboxylates - Google Patents

Method for preparing 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole-4-carbaldehydes and 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole-4-carboxylates Download PDF

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WO2015110493A1
WO2015110493A1 PCT/EP2015/051184 EP2015051184W WO2015110493A1 WO 2015110493 A1 WO2015110493 A1 WO 2015110493A1 EP 2015051184 W EP2015051184 W EP 2015051184W WO 2015110493 A1 WO2015110493 A1 WO 2015110493A1
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alkyl
pyrazole
difluoromethyl
carbaldehydes
fluor
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PCT/EP2015/051184
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French (fr)
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Norbert Lui
Sergii Pazenok
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Bayer Cropscience Ag
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Priority to JP2016547519A priority Critical patent/JP6462703B2/en
Priority to DK15700749.3T priority patent/DK3097081T3/en
Priority to BR112016016397-4A priority patent/BR112016016397B1/en
Priority to KR1020167023073A priority patent/KR102319577B1/en
Priority to CN201580005766.1A priority patent/CN105934430B/en
Priority to MX2016009325A priority patent/MX361770B/en
Priority to ES15700749.3T priority patent/ES2657424T3/en
Priority to US15/113,377 priority patent/US9656966B2/en
Priority to EP15700749.3A priority patent/EP3097081B1/en
Publication of WO2015110493A1 publication Critical patent/WO2015110493A1/en
Priority to IL246870A priority patent/IL246870B/en

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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
    • C07D231/14—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 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
    • C07D231/16—Halogen atoms or nitro radicals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles

Definitions

  • the present invention relates to a novel method for preparing l-alkyl-3-difluoromethyl -5-fluor-lH- pyrazole-4-carbaldehydes or esters thereof of formula (I) by means of reductive dehalogenation, starting from l-alkyl-3-chlorodifluoromethyl-5-fluoro-lH-pyrazole-4-carbaldehydes or esters thereof of formula (II)
  • R is Ci-C6-alkyl and R is H or Ci-C6-alkoxy.
  • l-Alkyl-3-haloalkyl-5-fluoropyrazolecarbaldehydes and esters thereof are important building blocks for preparing plant protection active ingredients, particularly SDHI fungicides.
  • l-Alkyl-3-difluoromethyl-5-fluor-lH-pyrazole-4-carbaldehydes was so far typically prepared in a multi-stage transformation starting from difluoromethylacetoacetate (WO 2011061205) :
  • WO 2013/171134 shows the reductive elimination of the halogen atom in position 5 of 5-chloro-l-alkyl-3-difluormethylcarbaldehyde
  • WO 2004/063165 describes the removal of a chlorine atom in N-aryl-3-methyl-5-chloropyrazole- carbaldehydes.
  • R is Ci-C6-alkyl and R is H or Ci-C6-alkoxy
  • the radical R 1 is preferably methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, particularly preferably methyl or ethyl, even more preferably methyl.
  • the reaction is carried out in the presence of hydrogen. It is possible to use either pure hydrogen or mixtures of hydrogen and an inert gas (up to 1 : 1), such as nitrogen or argon.
  • the reaction is carried out at pressures of 1 bar to 50 bar, preferably 1 bar to 20 bar and particularly preferably 2 bar to 15 bar.
  • a base is optionally added.
  • an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, mono-, di- or trisodium phosphate or tripotassium phosphate, sodium hydroxide or potassium hydroxide or an organic base such as triethylamine, tributylamine, diazabicycloun- decene (DBU), diazabicyclononene (DBN), pyridine, lutidine, 2-, 3- or 4-picoline or diazabicyclooc- tane (DABCO) can be used.
  • DBU diazabicycloun- decene
  • DBN diazabicyclononene
  • pyridine lutidine, 2-, 3- or 4-picoline or diazabicyclooc- tane
  • DABCO diazabicyclooc- tane
  • any hydrogena- tion catalyst may be used as catalyst.
  • Suitable catalysts include optionally one or more metals from groups 8 - 10 of the periodic table on any conventional inorganic support. Examples include noble metal catalysts, such as ruthenium catalysts, palladium catalysts, platinum catalysts and rhodium catalysts, Raney nickel catalysts and Raney cobalt and Lindlar catalysts.
  • noble metal catalysts such as ruthenium catalysts, palladium catalysts, platinum catalysts and rhodium catalysts, Raney nickel catalysts and Raney cobalt and Lindlar catalysts.
  • hydrogenations over homogeneous catalysts can, however, also be carried out, for example over the Wilkinson catalyst.
  • the relevant catalysts may be used in supported form, for example on carbon (charcoal or activated charcoal), aluminium oxide, silicon dioxide, zirconium dioxide, calcium carbonate or titanium dioxide. Catalysts of this kind are known per se to those skilled in the art. Particularly preferred are palladium catalysts supported on calcium carbonate.
  • the catalysts may be used either in water-moist or in dried form.
  • the catalyst used is preferably reused for a plurality of conversions.
  • the catalyst is used at a concentration of approximately 0.01 to approximately 30% by weight, based on the halo-l-alkyl-3-fluoroalkyl-lH- pyrazole-4-carbaldehyde of the formula (II) used.
  • the catalyst is preferably used at a concentration of approximately 0.1 to approximately 5% by weight.
  • the reduction is advantageously carried out in the presence of at least of one additive.
  • Typical additives are, NELtOAc, Sodium Acetate, MgF2, NH 4 F, AIF 3 , K2CO3, Borax.
  • the reaction time may be up to 20 hours, depending on the reactivity of the reactants, while the reac- tion can also be terminated earlier when conversion is complete. Preference is given to reaction times of 3-10 hours.
  • the reaction is carried out in the presence of a solvent.
  • Suitable solvents are: alcohols, ethyl acetate, isopropyl acetate, THF, methyltetrahydrofuran, dioxane, toluene, hexane, heptane, pentane or petroleum ether. Particular preference is given to the use of methanol, ethanol, DMSO, dimethylacetamide, DMF or NMP.
  • 5-Fluoro-l-alkyl-3-chlorodifluoroalkyl-lH-pyrazole-4-carbaldehydes of the formula (Ila) can be prepared by known methods (cf. /. Het. Chem. 1990, 27, 243, WO 2006/018725 Al, WO 2011/061205 Al, B. Hamper et al. Journal of Organic Chemistry V.57,N21,5680-6, WO 2011061205, WO2013171134 and WO2011131615).
  • R 1 and R 3 are independently Cl-C6-alkyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The present invention relates to a novel method for preparing 1-alkyl-3-difluoromethyl-5-fluor-1H-pyrazole-4-carbaldehydes or esters thereof of formula (I) by means of reductive dehalogenation, starting from 1-alkyl-3-chlorodifluoromethyl-5-fluoro-1H-pyrazole-4-carbaldehydes or esters thereof Formula (I).

Description

Method for preparing l-alkyl-3-difluoromethyl-5-fluor-lH-pyrazole-4-carbaldehvdes and l-alkyl-3-difluoromethyl-5-fluor-lH-pyrazole-4-carboxylates
The present invention relates to a novel method for preparing l-alkyl-3-difluoromethyl -5-fluor-lH- pyrazole-4-carbaldehydes or esters thereof of formula (I) by means of reductive dehalogenation, starting from l-alkyl-3-chlorodifluoromethyl-5-fluoro-lH-pyrazole-4-carbaldehydes or esters thereof of formula (II)
Figure imgf000003_0001
wherein R is Ci-C6-alkyl and R is H or Ci-C6-alkoxy. l-Alkyl-3-haloalkyl-5-fluoropyrazolecarbaldehydes and esters thereof are important building blocks for preparing plant protection active ingredients, particularly SDHI fungicides. l-Alkyl-3-difluoromethyl-5-fluor-lH-pyrazole-4-carbaldehydes was so far typically prepared in a multi-stage transformation starting from difluoromethylacetoacetate (WO 2011061205) :
Figure imgf000003_0002
Starting material for this transformation, i.e.ethyldifluoracetoacetate, is a rather unstable compound, difficult to purify and which loses its quality during storage. This makes the utilization of this compound, especially on industrial scale, difficult.
The transformation of pyrazolic compounds bearing CF2H group is a challenging task as well, since this group is rather unstable under acidic conditions and easily releases fluoride which can damage reaction vessel, especially on a technical scale. A process for the preparation of esters of l-alkyl-3-fluoroalkylpyrazole-carboxylic acids via the reduction of 3-chlorodifluoromethylpyrazolic caboxylates was known from WO 2012/010692. Nevertheless, it was not known nor expected that a reductive dehalogenation of CFiCl-group can occur in pyrazoles bearing a halogen atom in position 5 or a carbaldehyde function in position 4 without un- desirable effect on said halogen atom in position 5 or carbaldehyde function in position 4. On con- trario, the skilled man would expect that the aldehyde group will also at least partially react, and/or that the fluorine atom in position 5 will also at least partially react, as it is shown or suggested in WO 2013/171134 and WO 2004/063165. Indeed WO 2013/171134 shows the reductive elimination of the halogen atom in position 5 of 5-chloro-l-alkyl-3-difluormethylcarbaldehyde, and WO 2004/063165 describes the removal of a chlorine atom in N-aryl-3-methyl-5-chloropyrazole- carbaldehydes.
It has now surprisingly been found that, under the conditions of the invention, it is possible to selectively remove a halogen atom from a chlorodifluoromethyl group in l-alkyl-3-chlorodifluoromethyl- 5-fluoro-lH-pyrazole-4-carbaldehydes of formula (Ila) or l-alkyl-3-chlorodifluoromethyl-5-fluor- lH-pyrazole-4-carboxylates of formula (lib), without affecting or reducing the fluorine atom in position 5, without reducing the carbaldehyde or carboxylate group in position 4 and without attacking the pyrazole ring.
It has also surprisingly been found that the reductive dehalogenation of 5-Fluoro-l-alkyl-3- chlorodifluoroalkyl-lH-pyrazole-4-carbaldehydes and esters thereof leads selectively and in high yield to the l-alkyl-3-difluoromethyl- 5-fluoro-lH-pyrazole-4-carbaldehydes and esters thereof.
It has now been found that l-alkyl-3-difluoromethyl -5-fluor-lH-pyrazole-4-carbaldehydes or esters thereof of formula (I)
Figure imgf000004_0001
wherein R is Ci-C6-alkyl and R is H or Ci-C6-alkoxy,
can be obtained by reacting 5-fluoro-l-alkyl-3-chlorodifluoromethyl -5-fluoro-lH-pyrazole-4- carbaldehydes or esters thereof of formula (II)
Figure imgf000005_0001
wherein R and R are as stated above, by means of catalytic hydrogenation and optionally in the presence of a base. It has now been found that l-alkyl-3-difluoromethyl-lH-pyrazole-4-carbaldehydes of formula (la) or l-alkyl-3-difluoromethyl-5-fluoro-lH-pyrazole-4-carboxylates of formula (lb)
Figure imgf000005_0002
(la) (lb) where R1 is Ci-C6-alkyl, and R2 is Ci-C6-alkoxy, can be obtained by reacting 5-fluoro-l-alkyl-3-chlorodifluoromethyl -5-fluoro-lH-pyrazole-4- carbaldehydes of formula (Ila) or l-alkyl-3-chlorodifluoromethyl-5-fluor-lH-pyrazole-4-carboxylates of formula (lib) respectively
Figure imgf000005_0003
(Ila) (lib) where R1 , R2 have the meanings stated above, by means of catalytic hydrogenation and optionally in the presence of a base.
The method according to the invention may be illustrated by the following formula schemes:
Figure imgf000006_0001
(Hb) (lb)
Figure imgf000006_0002
(Ha) (la) where R1 is Ci-C6-alkyl, and R2 is Ci-C6-alkoxy.
The radical R1 is preferably methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, particularly preferably methyl or ethyl, even more preferably methyl.
5-Fluoro-l-methyl-3-difluoromethyl-lH-pyrazole-4-carbaldehyde (IT1) or esters thereof and 5- Fluo- ro-l-ethyl-3-difluoromethyl-lH-pyrazole-4-carbaldehyde (II-2) or ester thereof are very particularly preferably used as starting material.
The reaction is carried out in the presence of hydrogen. It is possible to use either pure hydrogen or mixtures of hydrogen and an inert gas (up to 1 : 1), such as nitrogen or argon. The reaction is carried out at pressures of 1 bar to 50 bar, preferably 1 bar to 20 bar and particularly preferably 2 bar to 15 bar.
To scavenge the hydrogen chloride, formed during the reaction, a base is optionally added. As added base, either an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, mono-, di- or trisodium phosphate or tripotassium phosphate, sodium hydroxide or potassium hydroxide or an organic base such as triethylamine, tributylamine, diazabicycloun- decene (DBU), diazabicyclononene (DBN), pyridine, lutidine, 2-, 3- or 4-picoline or diazabicyclooc- tane (DABCO) can be used. Preference is given to the use of triethylamine. 0.5 to 20 molar equiva- lents, preferably 0.5 to 5 molar equivalents and particularly preferably 1 to 5 molar equivalents of the base are added, based on the substrate.
In the catalytic hydrogenation for reducing the compound of the general formula (II), any hydrogena- tion catalyst may be used as catalyst. Suitable catalysts include optionally one or more metals from groups 8 - 10 of the periodic table on any conventional inorganic support. Examples include noble metal catalysts, such as ruthenium catalysts, palladium catalysts, platinum catalysts and rhodium catalysts, Raney nickel catalysts and Raney cobalt and Lindlar catalysts. In addition to these heterogene- ous catalysts, hydrogenations over homogeneous catalysts can, however, also be carried out, for example over the Wilkinson catalyst. The relevant catalysts may be used in supported form, for example on carbon (charcoal or activated charcoal), aluminium oxide, silicon dioxide, zirconium dioxide, calcium carbonate or titanium dioxide. Catalysts of this kind are known per se to those skilled in the art. Particularly preferred are palladium catalysts supported on calcium carbonate. The catalysts may be used either in water-moist or in dried form. The catalyst used is preferably reused for a plurality of conversions. In the method according to the invention, the catalyst is used at a concentration of approximately 0.01 to approximately 30% by weight, based on the halo-l-alkyl-3-fluoroalkyl-lH- pyrazole-4-carbaldehyde of the formula (II) used. The catalyst is preferably used at a concentration of approximately 0.1 to approximately 5% by weight.
In the process according to the invention, the reduction is advantageously carried out in the presence of at least of one additive. Typical additives are, NELtOAc, Sodium Acetate, MgF2, NH4F, AIF3, K2CO3, Borax. Especially K2C03, NH4C1, NH4F, CsF or Borax.
The reaction time may be up to 20 hours, depending on the reactivity of the reactants, while the reac- tion can also be terminated earlier when conversion is complete. Preference is given to reaction times of 3-10 hours.
The reaction is carried out in the presence of a solvent. Suitable solvents are: alcohols, ethyl acetate, isopropyl acetate, THF, methyltetrahydrofuran, dioxane, toluene, hexane, heptane, pentane or petroleum ether. Particular preference is given to the use of methanol, ethanol, DMSO, dimethylacetamide, DMF or NMP.
5-Fluoro-l-alkyl-3-chlorodifluoroalkyl-lH-pyrazole-4-carbaldehydes of the formula (Ila) can be prepared by known methods (cf. /. Het. Chem. 1990, 27, 243, WO 2006/018725 Al, WO 2011/061205 Al, B. Hamper et al. Journal of Organic Chemistry V.57,N21,5680-6, WO 2011061205, WO2013171134 and WO2011131615).
The preparation of compounds could be performed according to the following schema.
Figure imgf000008_0001
where R1 and R3 are independently Cl-C6-alkyl.
Preparation examples Example 1 l-methyl-3-difluoromethyl-5-fluoro-lH-pyrazole-4-carbaldehyde .
Figure imgf000008_0002
In an autoclave 10 g of 5-chloro-3-(difluorochlormethyl)-l-methyl-lH-pyrazole-4-carbaldehyde dissolved in 150 ml of THF and 10 g triethylamin and 500 mg of 5 % palladium on calcium carbonate were added. The autoclave was flushed with nitrogen and pressurised to 15 bar hydrogen. Reaction mixture in autoclave was stirred at 90°C for 6 h. After filtration of the catalyst, the solvent was removed under reduced pressure and the product was obtained as a solid and purified via crystallization from mixture isopropanol/water. Yield 7 g , melting point 68-69°C
Example 2
In an autoclave 10 g of 5-chloro-3-(difluorochlormethyl)-l-methyl-lH-pyrazole-4-carbaldehyde dissolved in 150 ml of THF and 10 g CsF and 400 mg of 150 mg Pd(OH)2 on carbon were added. The autoclave was flushed with nitrogen and pressurised to 15 bar hydrogen. Reaction mixture in auto- clave was stirred at 90°C for 6 h. After filtration of the catalyst, the solvent was removed under re- duced pressure and the product was obtained as a solid and purified via crystallization from mixture isopropanol/water. Yield 7 g, melting point 68-69°C
Example 3.
Ethyl l-methyl-3-difluormethyl-5-fluoro-lH-pyrazole-4-carboxylate
Figure imgf000009_0001
In an autoclave 10,5 g of Ethyl l-methyl-3-chlorodifluormethyl-5-fluoro-lH-pyrazole-4- carboxylate in 100 ml of THF, 6 g Potassium carbonate and 150 mg Pd(OH)2 on carbon support were added. The autoclave was flushed with nitrogen and pressurised to 15 bar hydrogen. Reaction mixture in autoclave was stirred at 100°C for 6 h. After filtration of the catalyst, the solvent was re- moved under reduced pressure and the product was obtained as a solid and purified via crystallization from mixture isopropanol/water. Yield 7.2 g.

Claims

Claims
1. Process for preparing l-alkyl-3-difluoromethyl -5-fluor-lH-pyrazole-4-carbaldehydes or esters thereof of formula I
Figure imgf000010_0001
(I)
wherein R1 is Ci-C6-alkyl and R is H or Ci-C6-alkoxy,
characterized in that
5-fluoro-l-alkyl-3-chlorodifluoromethyl -5-fluoro-lH-pyrazole-4-carbaldehydes or esters thereof of formula (II)
Figure imgf000010_0002
(I I)
wherein R and R1 are as stated above,
is reacted by means of catalytic hydrogenation.
2. The process according to claim 1 wherein R1 is methyl, ethyl, n-propyl, isopropyl, butyl or pentyl.
3. The process according to claim 2 wherein R1 is methyl or ethyl.
4. The process according to claim 3 wherein R1 is methyl.
5. The process according to any ones of claims 1 to 4 wherein the catalytic hydrogenation is done in presence of a base.
6. The process according to claim 5 wherein the base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, mono-, di- or trisodium phosphate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, triethylamine, tributylamine, diazabicycloundecene (DBU), diazabicyclononene (DBN), pyridine, lutidine, 2-, 3- or 4-picoline or diazabicyclooctane (DABCO).
7. The process according to claim 5 wherein the base is triethylamine.
PCT/EP2015/051184 2014-01-24 2015-01-22 Method for preparing 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole-4-carbaldehydes and 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole-4-carboxylates WO2015110493A1 (en)

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JP2016547519A JP6462703B2 (en) 2014-01-24 2015-01-22 Process for preparing 1-alkyl-3-difluoromethyl-5-fluoro-1H-pyrazole-4-carbaldehydes and 1-alkyl-3-difluoromethyl-5-fluoro-1H-pyrazole-4-carboxylates
DK15700749.3T DK3097081T3 (en) 2014-01-24 2015-01-22 PROCEDURE FOR PREPARING 1-ALKYL-3-DIFLUORMETHYL-5-FLUOR-1H-PYRAZOL-4-CARBALDEHYDER AND 1-ALKYL-3-DIFLUORMETHYL-5-FLUOR-1H-PYRAZYL-4-CARBOXYL
BR112016016397-4A BR112016016397B1 (en) 2014-01-24 2015-01-22 PROCESS TO PREPARE 1-ALKYL-3-DIFLUOROMETHYL-5-FLUORO-1H-PYRAZOL-4-CARBALDEHYDES OR ITS ESTERS
KR1020167023073A KR102319577B1 (en) 2014-01-24 2015-01-22 Method for preparing 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole-4-carbaldehydes and 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole-4-carboxylates
CN201580005766.1A CN105934430B (en) 2014-01-24 2015-01-22 The method for preparing the formaldehyde of 1 alkyl, 3 difluoromethyl, 5 fluorine 1H pyrazoles 4 and the formic acid esters of 1 alkyl, 3 difluoromethyl, 5 fluorine 1H pyrazoles 4
MX2016009325A MX361770B (en) 2014-01-24 2015-01-22 Method for preparing 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole -4-carbaldehydes and 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole -4-carboxylates.
ES15700749.3T ES2657424T3 (en) 2014-01-24 2015-01-22 Preparation procedure for 1-alkyl-3-difluoromethyl-5-fluor-1H-pyrazol-4-carbaldehydes and 1-alkyl-3-difluoromethyl-5-fluorine-1H-pyrazole-4-carboxylates
US15/113,377 US9656966B2 (en) 2014-01-24 2015-01-22 Method for preparing 1-alkyl-3-difluoromethyl-5-fluor-1H-pyrazole-4-carbaldehydes and 1-alkyl-3-difluoromethyl-5-fluor-1H-pyrazole-4-carboxylates
EP15700749.3A EP3097081B1 (en) 2014-01-24 2015-01-22 Method for preparing 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole-4-carbaldehydes and 1-alkyl-3-difluoromethyl-5-fluor-1h-pyrazole-4-carboxylates
IL246870A IL246870B (en) 2014-01-24 2016-07-21 Method for preparing 1-alkyl-3-difluoromethyl-5-fluoro-1h-pyrazole-4-carbaldehydes and 1-alkyl-3-difluoromethyl-5-fluoro-1h-pyrazole-4-carboxylates

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WO2022233129A1 (en) 2021-05-05 2022-11-10 Fujian Yongjing Technology Co., Ltd New process for the synthesis of 5-fluoro-3- (difuoromethyl) -5-fluoro-1-methyl-1h-pyrazole-4-carboxylic acid derivatives and the free acid thereof

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TWI782599B (en) * 2020-07-02 2022-11-01 美商輝瑞股份有限公司 Aminopyrimidinyl derivatives
TWI785660B (en) * 2020-07-02 2022-12-01 美商輝瑞大藥廠 Preparation of a pyrimidinyl-3,8-diazabicyclo[3.2.1]octanylmethanone derivative and salt thereof

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