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WO2015155713A1 - Procédé de synthèse régiosélective de pyrazoles substitués en positions 1,3,4 - Google Patents

Procédé de synthèse régiosélective de pyrazoles substitués en positions 1,3,4 Download PDF

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Publication number
WO2015155713A1
WO2015155713A1 PCT/IB2015/052557 IB2015052557W WO2015155713A1 WO 2015155713 A1 WO2015155713 A1 WO 2015155713A1 IB 2015052557 W IB2015052557 W IB 2015052557W WO 2015155713 A1 WO2015155713 A1 WO 2015155713A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
difluoro
butanoate
oxo
Prior art date
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PCT/IB2015/052557
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English (en)
Inventor
Giovanni Meazza
Pierangelo MEREGHETTI
Laura Sillani
Daniele Forgia
Paolo Bellandi
Original Assignee
Isagro S.P.A.
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Publication date
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Publication of WO2015155713A1 publication Critical patent/WO2015155713A1/fr

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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

Definitions

  • the present invention relates to a new process for the regio selective synthesis of 1,3,4- substituted pyrazoles.
  • the present invention relates to a process for the regioselective synthesis of derivatives of l-alkyl-3-difluoromethyl-4-pyrazolecarboxylic acids.
  • 1,3,4-substituted pyrazoles are used as intermediates in the pharmaceutical industry, as described, for example, in Pharmaceuticals (2012), vol.5, pages 317-324, WO 2004/4039365, US 2012/0122907, US 2013/0012715, US 2006/0079562, or in the agrochemical industry, as described for example in US 5,747,518, WO 93/11117, WO 2012/084812.
  • 1,3-disubstituted 4-pyrazolecarboxylic acids are of particular applicative interest. These compounds are normally prepared by the cyclization of suitable derivatives of acrylic acid with monosubstituted hydrazines, as indicated in reaction scheme A:
  • Y represents oxygen or sulphur
  • Q represents a leaving group, such as for example an alkoxyl
  • Z represents in general an alkoxycarbonyl group
  • R a and R represent the desired substituents in position 1 and 3 of the pyrazole.
  • the disadvantage of this method consists in the fact that significant quantities of 1,4,5-substituted pyrazole regioisomer are generally formed.
  • R a represents an alkyl group
  • the preparation of 1,3,4-substituted pyrazoles can also be effected by reaction between a suitable derivative of acrylic acid and hydrazine, followed by an alkylation reaction with a compound having formula R a -LG, wherein LG represents a leaving group such as, for example, a halogen, in order to introduce the alkyl group onto the nitrogen atom in position 1, as indicated in reaction scheme B:
  • N-alkylation reaction of pyrazoles is not regio selective and leads to the formation of mixtures of the two pyrazole isomers, as described, for example, in the Australian Journal of Chemistry (1983), vol. 36, pages 135- 147, in which the reaction of ethyl 3 -methyl- lH-pyrazole-4-carboxylate with methyl iodide in ethanol leads to the formation of ethyl l,3-dimethyl- lH-pyrazole-4-carboxylate in a 1 : 1 mixture with the 1,4,5- substituted regioisomer.
  • a 1,3,4-substituted pyrazole can be obtained with an extremely high regioselectivity with respect to the 1,4,5 isomer (higher than 95:5), by reacting the acrylic derivative with a mixture comprising a monosubstituted alkyl-hydrazine and a suitable organic compound containing at least two heteroatoms selected from oxygen, nitrogen and sulphur.
  • An object of the present invention therefore relates to a process for the synthesis of pyrazoles having general formula (I)
  • step b) the mixture obtained in step a) is reacted with a compound having formula (IV), obtaining a 1,3,4-substituted pyrazole having general formula (I), according to the reaction scheme 1
  • R represents a Ci-C 4 alkyl group
  • Ri represents a Ci-C 4 alkyl group or a Ci-C 4 haloalkyl group
  • R 2 represents a Ci-C 4 alkyl group
  • Xi and X 2 equal to or different from each other, represent an oxygen atom, a sulphur atom, or a N-RN group;
  • Rxi, R x2 , RN equal to or different from each other, represents a Ci-C 4 alkyl group, a C 2 -C 4 alkoxyalkyl group; or R x i and R x2 together, represent a C 2 alkylene (ethylene); when both Xi and X 2 represent a N-RN group, both R together represent a C 2 alkylene (ethylene);
  • R x represents a Ci-C 2 alkylene, optionally substituted by one or more groups selected from Ci-C 4 alkyl groups, Ci-C 4 alkoxyl groups, a C 6 -Cio aryl group substituted in vicinal positions by R X i-Xi- and Rx 2 -X 2 - groups, equal to or different from each other, a tetrahydrofuranyl group substituted in vicinal positions or in positions 2,5 by Rxi-Xi- and Rx 2 - X 2 - groups, equal to or different from each other.
  • Ci-C 4 alkyl group examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl.
  • Ci-C 4 haloalkyl group examples are difluoromethyl, trifluoromethyl, 1,1- dichloroethyl, 1,1,1-trifluoroethyl, 1,1,2,2-tetrafluoropropyl, 1,1,1,2,2-pentafluoropropyl, 1,1- dichlorobutyl, 1,1-difluorobutyl.
  • Ci-C 4 alkoxyl group examples include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy.
  • Examples of a C 2 -C 4 alkoxyalkyl group are methoxy-methyl, methoxyethyl, methoxypropyl, ethoxyethyl.
  • Ci-C 2 alkylene examples include methylene, ethylene.
  • Examples of a C 6 -Cio aryl group are phenyl, naphthyl.
  • - Ri represents a Ci-C 4 alkyl group
  • step a) for the preparation of the mixture the alkyl-hydrazine (II) and the compound having formula (III) are kept in a mixture, optionally in the presence of a solvent, for a minimum time that can vary in relation to the compounds having formula (II) and (III) used, the temperature at which the mixture is maintained, the solvent possibly used.
  • the solvent that can be used in step a) of the process is preferably an aromatic hydrocarbon such as toluene, xylene, benzene, or tetrahydrofuran, preferably toluene.
  • the mixture is normally maintained, under stirring or possibly without stirring, at a temperature within the range of 10°C to 30°C, preferably from 15°C to 25°C, for a minimum time ranging from 6 to 24 hours, preferably from 12 to 18 hours, before proceeding with the subsequent step b) of the process according to the present invention.
  • the compounds having formula (II) and (III) are used in a molar ratio that can vary from an equimolar ratio of 1 : 1, to a ratio in which the product having formula (III) is in a molar ratio of 1.5: 1 with respect to the alkyl -hydrazine (II).
  • step b) of the process according to the present invention the mixture of compounds having formula (II) and (III) is reacted with the compound having formula (IV), preferably in the same solvent possibly used for the preparation of the mixture of compounds (II) and (III).
  • step b the temperature of the reaction mixture is normally maintained within the range of 10 to 30°C.
  • Step b) of the process can be carried out by adding the mixture of compounds (II) and (III), possibly dissolved in a suitable solvent, to the compound having formula (IV), possibly dissolved in a suitable solvent.
  • step b) can be carried out by adding compound (IV), possibly dissolved in a suitable solvent, to the mixture of compounds (II) and (III), possibly dissolved in a suitable solvent.
  • Step b) of the process is preferably carried out by adding the compound having formula (IV) possibly dissolved in a suitable solvent to the mixture of compounds (II) and (III), kept under bland stirring and possibly dissolved in a suitable solvent.
  • the mixture of compounds (II) and (III) and the compound having formula (IV) are dissolved in the same solvent.
  • the solvent that can be used in step b) of the process is preferably an aromatic hydrocarbon such as toluene, xylene, benzene, or tetrahydrofuran, preferably toluene.
  • step a) and step b) are normally carried out at atmospheric pressure, but can also be carried out, independently of each other, at a lower or higher pressure than atmospheric pressure.
  • the compounds having formula (II) and (IV) are generally used in a molar ratio that can vary from 0.9: 1 to 1.1 : 1, and are preferably used in a substantially equimolar ratio.
  • the molar ratio between the compounds having formula (II) and (III) is extremely important for obtaining a high regio selectivity in the process according to the present invention which comprises the condensation/cyclization reaction of alkyl-hydrazines (II) with compounds having formula (IV).
  • the pyrazoles having formula (I) can be isolated and purified according to methods known in the practice of organic chemistry, on both a laboratory scale and in industrial plants.
  • the reaction mixture of step b), for example, can be concentrated at reduced pressure, thus enabling the recovery and recycling of the solvent and compound having formula (III), whereas the residue can be purified or hydrolyzed directly to l-alkyl-3-difluoromethyl-4- pyrazolecarboxylic acid, which can be obtained in a high yield and high purity by crystallization.
  • the compounds having formula (II) and (III) used for the process according to the present invention are generally products available on the market.
  • the preferred compound having formula (II) in the process according to the present invention is methyl-hydrazine.
  • Examples of compounds having formula (III) which can be used in the process according to the present invention are: dimethoxy-methane, 1,2-dimethoxy-propane, 2,2-dimethoxy- propane, 1,2-dimethoxy-ethane, 1,1-diethoxy-ethane, 1,2-diethoxy-ethane, 1,4-dioxane, bis-(2- methoxyethyl)ether, poly(ethyleneglycol)-dimethylether, 1,2-dimethoxy-benzene, 2,5- dimethoxy-tetrahydrofuran, ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylethylene-diamine, 1,4-diazobicyclooctane, tris(3,6-dioxo-heptyl)amine, N-methyl-morpholine, 1,3-dithiane.
  • Preferred compounds having formula (III) in the process according to the present invention are compounds having formula (III) wherein Xi and X 2 both represent an oxygen atom.
  • the compounds having formula (IV) can be prepared according to what is described, for example, in "Organic and Biomolecular Chemistry” (2009), vol. 7, pages 2182-2186.
  • Examples of compounds having formula (IV) that can be used in the process according to the present invention are methyl 2-(methoxymethylidene)-4,4-difluoro-3-oxo-butanoate, ethyl 2- (methoxymethylidene)-4,4-difluoro-3-oxo-butanoate, methyl 2-(ethoxymethylidene)-4,4- difluoro-3-oxo-butanoate, ethyl 2-(ethoxy-methylidene)-4,4-difluoro-3-oxo-butanoate, trifluoroethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate, propyl 2-
  • Preferred compounds having formula (IV) are methyl 2-(ethoxymethylidene)-4,4- difluoro-3-oxo-butanoate, ethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate, butyl 2- (ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate.
  • the compound having formula (IV) which is particularly preferred is ethyl 2- (ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate.
  • ester derivatives of 3-difluoromethyl-l-methyl-4-pyrazolecarboxylic acid which is an extremely important intermediate for the synthesis of products having a high fungicidal activity used in the agrochemical field, can be obtained with high yields and a high purity.
  • Methyl-hydrazine (0.71 ml) is dripped into a solution of 1,2-dimethoxyethane (2.1 ml) in 9.0 ml of toluene and the mixture is left under moderate stirring for a night (18 hours) at room temperature. The mixture is then cooled to 10°C and ethyl 2-(ethoxymethylidene)-4,4-difluoro- 3-oxo-butanoate (3.0 g), dissolved in 4.5 ml of toluene, is then added. The mixture is left to react at room temperature for two hours.
  • Methyl-hydrazine (0.48 ml) is added to a solution of 2,2-dimethoxypropane (1.66 ml) in 3.0 ml of toluene and the mixture is left under moderate stirring for 8 hours. The solution is then cooled to 10°C and ethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxo-butanoate (2.0 g), dissolved in 1.5 ml of toluene, is then added. The mixture is left under stirring at room temperature for 12 hours.
  • Ethyl 2-(ethoxy-methylidene)-4,4-trifluoro-3-oxo-butanoate (2.0 g) is added dropwise to a solution of 1-methyl-hydrazine (0.48 ml) in 11 ml of 2,2-dimethoxypropane, cooled to 10°C; the mixture is kept under stirring at room temperature for 12 hours.
  • Example 1 Following the procedure described in Example 1, the compound (1- 1) was prepared starting from the mixture (methylhydrazine + 1,2-dimethoxyethane) and ethyl 2- (ethoxymethylidene)-4,4-difluoro-3-oxobutanoate, alternatingly using xylene and tetrahydrofuran as solvents, instead of the toluene adopted in Example 1.
  • Table 1 indicates the compounds having formula (III) and the solvents used, the temperature range of step b), the regioselectivities obtained.
  • 1,3-dithiane toluene 95.1 rs represents the regioselectivity in the isomer (I).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé pour la synthèse de pyrazoles de formule générale (I), comprenant les étapes suivantes : a) préparer un mélange comprenant une alkylhydrazine de formule (II) RNH-NH2 et un composé de formule générale (III) Rx1-X1-Rx-X2-Rx2; b) faire réagir le mélange obtenu dans l'étape a) avec un composé de formule (IV), ce qui permet d'obtenir un pyrazole substitué en positions 1,3,4 de formule générale (I), selon le schéma réactionnel 1.
PCT/IB2015/052557 2014-04-09 2015-04-08 Procédé de synthèse régiosélective de pyrazoles substitués en positions 1,3,4 WO2015155713A1 (fr)

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ITMI2014A000670 2014-04-09

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3650443A1 (fr) * 2018-11-07 2020-05-13 Fujian Yongjing Technology Co., Ltd. Synthèse en flux continu de pyrazoles fluorés ou non fluorés

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011117A1 (fr) 1991-12-06 1993-06-10 Monsanto Company Fongicides a base de carboxanilide de pyrazole
US5747518A (en) 1995-04-11 1998-05-05 Mitsui Toatsu Chemicals, Inc. Substituted thiophene derivative and agricultural and horticultural fungicide containing the same as active ingredient
WO2004039365A1 (fr) 2002-11-01 2004-05-13 Takeda Pharmaceutical Company Limited Agent pour la prévention ou le traitement de neuropathie
US20060079562A1 (en) 2004-10-12 2006-04-13 Ewing William R Heterocyclic aromatic compounds useful as growth hormone secretagogues
WO2008145257A1 (fr) * 2007-05-31 2008-12-04 Syngenta Participations Ag Procédé de fabrication de pyrazoles
EP2100883A1 (fr) * 2008-03-10 2009-09-16 Bayer CropScience AG Procédé de synthèse régiosélective de dérivés d'acides carboniques 1-alcyl-3-haloalcyl-pyrazol-4
US20120122907A1 (en) 2009-07-24 2012-05-17 Bolea Christelle Novel Pyrazole Derivatives and their use as Positive Allosteric Modulators of Metabotropic Glutamate Receptors
WO2012084812A1 (fr) 2010-12-20 2012-06-28 Isagro Ricerca S.R.L. Amides d'aminoindanes présentant une forte activité fongicide et leurs compositions phytosanitaires
US20130012715A1 (en) 2010-03-29 2013-01-10 Westfaelische Wilhelms Universitaet Muenster Pyrazole synthesis by coupling of carboxylic acid derivatives and enamines

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011117A1 (fr) 1991-12-06 1993-06-10 Monsanto Company Fongicides a base de carboxanilide de pyrazole
US5747518A (en) 1995-04-11 1998-05-05 Mitsui Toatsu Chemicals, Inc. Substituted thiophene derivative and agricultural and horticultural fungicide containing the same as active ingredient
WO2004039365A1 (fr) 2002-11-01 2004-05-13 Takeda Pharmaceutical Company Limited Agent pour la prévention ou le traitement de neuropathie
US20060079562A1 (en) 2004-10-12 2006-04-13 Ewing William R Heterocyclic aromatic compounds useful as growth hormone secretagogues
WO2008145257A1 (fr) * 2007-05-31 2008-12-04 Syngenta Participations Ag Procédé de fabrication de pyrazoles
EP2100883A1 (fr) * 2008-03-10 2009-09-16 Bayer CropScience AG Procédé de synthèse régiosélective de dérivés d'acides carboniques 1-alcyl-3-haloalcyl-pyrazol-4
US20120122907A1 (en) 2009-07-24 2012-05-17 Bolea Christelle Novel Pyrazole Derivatives and their use as Positive Allosteric Modulators of Metabotropic Glutamate Receptors
US20130012715A1 (en) 2010-03-29 2013-01-10 Westfaelische Wilhelms Universitaet Muenster Pyrazole synthesis by coupling of carboxylic acid derivatives and enamines
WO2012084812A1 (fr) 2010-12-20 2012-06-28 Isagro Ricerca S.R.L. Amides d'aminoindanes présentant une forte activité fongicide et leurs compositions phytosanitaires

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AUSTRALIAN JOURNAL OF CHEMISTRY, vol. 36, 1983, pages 135 - 147
ORGANIC AND BIOMOLECULAR CHEMISTRY, vol. 7, 2009, pages 2182 - 2186
PHARMACEUTICALS, vol. 5, 2012, pages 317 - 324
RAW S A ET AL: "A one-pot process for the regioselective synthesis of 1,3,4-trisubstituted-1H-pyrazoles", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 50, no. 6, 11 February 2009 (2009-02-11), pages 696 - 699, XP025816789, ISSN: 0040-4039, [retrieved on 20081130], DOI: 10.1016/J.TETLET.2008.11.099 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3650443A1 (fr) * 2018-11-07 2020-05-13 Fujian Yongjing Technology Co., Ltd. Synthèse en flux continu de pyrazoles fluorés ou non fluorés

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