WO2023275705A1 - A process for the preparation of pyrazolopyridine-diamides of formula (i) and intermediates thereof - Google Patents

A process for the preparation of pyrazolopyridine-diamides of formula (i) and intermediates thereof Download PDF

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WO2023275705A1
WO2023275705A1 PCT/IB2022/055939 IB2022055939W WO2023275705A1 WO 2023275705 A1 WO2023275705 A1 WO 2023275705A1 IB 2022055939 W IB2022055939 W IB 2022055939W WO 2023275705 A1 WO2023275705 A1 WO 2023275705A1
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formula
compound
salt
group
methyl
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PCT/IB2022/055939
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English (en)
French (fr)
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Sanjay Maruti MADURKAR
Yuvraj Navanath KALE
Govind TOMAR
Dipak Jaysing DHAWADE
Pranab Kumar Patra
Alexander Gunther Maria KLAUSENER
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Pi Industries Ltd.
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Publication of WO2023275705A1 publication Critical patent/WO2023275705A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for the preparation of bicyclic anthranilic diamides of formula (I) and salts thereof. More particularly, the present invention relates to a process for preparing bicyclic anthranilic diamides of formula (I), comprising the step of preparing a substituted 2-(5-(2-cyanoprop- l-en-l-yl)-lH-pyrazol-l-yl)acetate of formula (VII) or salts thereof by reacting a substituted 2-(5- formyl-lH-pyrazol-l-yl)acetate of formula (VIII) or salts thereof with a substituted (1- cyanoethyl)phosphonate of formula (IX) or salts thereof.
  • the invention further relates to a process for preparing intermediates of formula (Z) or salts thereof, which are useful in the preparation of compound of formula (I) or salts thereof.
  • Fused bicyclic anthranilic diamides are reported in the article titled “Bicyclic heterocyclic anthranilic diamides as ryanodine receptor modulators with insecticidal activity” published in Bioorganic and Medicinal Chemistry 24 (2016) 403-427.
  • WO2019123195 discloses a compound of the following formula I providing bicyclic anthranilic diamides based on pyrazolo[l,5-a]pyridine-7-carboxamide derivatives, effective as insecticidal agents against harmful pests and useful as crop protecting agents.
  • WO2019123195 discloses a process that uses 2-(triphenylphosphanylidene)acetonitrile as a source of cyanoethylene and sodium hexamethyl disilazane (NaHMDS) as a base in the preparation of a certain alkyl 2-(5-(2-cyanoprop-l-en-l-yl)-lH-pyrazol-l-yl)acetate with 52% yield.
  • the said alkyl 2-(5-(2- cyanoprop-l-en-l-yl)-lH-pyrazol-l-yl)acetate is a key intermediate in the construction of the pyrazolo[l,5-a]pyridine core.
  • the present invention provides a simple, environment-friendly, and cost-effective process for the preparation of bicyclic anthranilic diamide compounds and intermediates thereof, based on readily available starting materials.
  • An objective of the present invention is to provide a simple, environment-friendly and cost-effective process for the preparation of bicyclic anthranilic diamides of formula (I) or of salts thereof.
  • Another objective of the present invention is to provide a process for preparing bicyclic anthranilic diamides of formula (I) or of salts thereof, comprising the step of preparing a substituted 2-(5-(2- cyanoprop-1-en-1-yl)-1H-pyrazol-1-yl)acetate of formula (VII) or a salt thereof by reacting a substituted 2-(5-formyl-1H-pyrazol-1-yl)acetate of formula (VIII) or a salt thereof with a substituted (1-cyanoethyl)phosphonate of formula (IX) or a salt thereof.
  • Yet another objective of the present invention is to provide a process for the preparation of compounds of formula (Z), that are useful intermediates in the preparation of bicyclic anthranilic diamide compounds of formula (I) or of salts thereof.
  • the present invention provides a process for preparing bicyclic anthranilic diamides of formula (I) or of salts thereof, wherein, R 1 and R 1a are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 - alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl and C 3 -C 6 -cycloalkyl; R a and R b are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 2 - C 6 -alkenyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -haloalkyl, C 3 -
  • reacting or “condensing” or “cyclising” or “hydrolysing” or “coupling” or “amidating” refers to a process of combining reactant(s) in a suitable medium or a solvent, wherein the reactants gets converted into desirable product(s) under reaction condition described.
  • a condition A “or” B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B is true (or present).
  • the indefinite articles “a” and “an” preceding an element or component of the present invention are intended to be non-restrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular. The meaning of various terms used in the description shall now be illustrated.
  • alkyl means a straight-chain or branched-chain C1 to C6 alkyl group and the representative examples include methyl, ethyl, propyl, isopropyl, butyl or the different isomers.
  • alkenyl means a straight-chain or branched C2 to C6 alkenes and the representative examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl or the different isomers.
  • cycloalkyl as used herein means alkyl closed to form a ring.
  • Representative examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • This definition also applies to cycloalkyl as a part of a composite substituent, for example cycloalkylalkyl etc., unless specifically defined elsewhere.
  • This definition also applies to cycloalkyl as a part of a composite substituent, for example halocycloalkyl group, wherein; a cycloalkyl group is partially or fully substituted with halogen atoms which may be the same or different.
  • halogen includes fluorine, chlorine, bromine or iodine and the term “haloalkyl”, as used herein means an alkyl group is partially or fully substituted with halogen atoms which may be the same or different.
  • haloalkyl include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro- 2-fluoroethyl, 2,2,2-trichloroethyl
  • the compounds synthesized by the novel and inventive process of the present invention may, if appropriate, be present as mixtures of different possible isomeric forms, especially of stereoisomers, for example E and Z, threo and erythro, and also optical isomers, but if appropriate also of tautomers. Both the E and the Z isomers, and also the threo and erythro isomers, and the optical isomers, any desired mixtures of these isomers and the possible tautomeric forms are disclosed and claimed.
  • the present invention provides a process for preparing bicyclic anthranilic diamides of formula (I) or a salt thereof, wherein, R 1 and R 1a are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 - alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl and C 3 -C 6 -cycloalkyl; R a and R b are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 2 - C 6 -alkenyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -halocycloalkyl, and C 3 -C 6 -cycloalkyl- C 1 -C 6 -alkyl; R 2 is selected from the group consisting of halogen, CHF 2 , CF 3
  • the present invention provides a process for the synthesis of a compound of formula (I) comprising the steps of: Reacting a compound of formula (VI) with a compound of formula (IV) in the presence of a suitable reagent to obtain a compound of formula (IIIA). Reacting the compound of formula (IIIA) with a suitable amine to obtain a compound of formula (I) as shown in the scheme below: .
  • the present invention provides an alternative process for preparing the compound of formula (V) comprising the steps of: cyclizing the compound of formula (VII) or a salt thereof, in the presence of a suitable base, and a suitable solvent to obtain a compound of formula (VI) or a salt thereof; which is reacted in situ with a suitable hydrolysing agent to obtain a compound of formula (V) or a salt thereof as shown in the scheme below: , wherein, R 1 , R 1a , R 6 , are each as defined above.
  • the present invention provides an alternative process for preparing the compound of formula (V) comprising the steps of: condensing the compound of formula (IX) or a salt thereof with a compound of formula (VIII) or a salt thereof, in the presence of a suitable base, and a suitable solvent to obtain a compound of formula (VII) or a salt thereof; which is reacted in situ with a suitable base to obtain a compound of formula (VI) or a salt thereof; which is reacted in situ with a suitable hydrolysing agent to obtain the compound of formula (V) or a salt thereof; as shown in the scheme below: , wherein, R 1 , R 1a , R 6 , are each as defined above.
  • the present invention provides a compound of formula (IIIA) wherein, R 1 and R 1a are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 - alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl and C 3 -C 6 -cycloalkyl;
  • R 2 is selected from the group consisting of halogen, CHF 2 , CF 3 , OCF 2 H, OCH 2 CF 3 , and ; wherein A represents CR c R c , NR c , O or S(O) 0-2 ;
  • R c is selected from the group consisting of hydrogen and C 1- C 4 -alkyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl;
  • R 6 is selected from the group consisting of hydrogen and C 1 -C 4 -al
  • the present invention provides a process for preparing bicyclic anthranilic diamides of formula (I), comprising the step of preparing a substituted 2-(5-(2-cyanoprop-1-en-1-yl)-1H-pyrazol- 1-yl)acetate of formula (VII) or a salt thereof, by reacting a substituted 2-(5-formyl-1H-pyrazol-1- yl)acetate of formula (VIII) or a salt thereof, with a substituted (1-cyanoethyl)phosphonate of formula (IX) or a salt thereof, in the presence of a suitable base and a suitable solvent.
  • the substituted acetonitrile of formula (X) is (R 1 CH 2 -CN) wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 3 -alkyl and C 1 -C 3 -haloalkyl.
  • the present invention provides a phosphorochloridate of formula (XI) or a salt thereof, wherein the preferred groups R 4 and R 5 are each independently selected as C 1 -C 3 -alkyl or R 4 and R 5 together with the O atom to which they are attached may form a 5-8-membered ring.
  • the present invention provides a compound of formula (IX) or a salt thereof, wherein the preferred group R 1 is selected from the group consisting of hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 - haloalkyl and C 3 -C 4 -cycloalkyl and R 4 and R 5 are each independently selected as C 1 -C 3 -alkyl or R 4 and R 5 together with the O atom to which they are attached may form a 5-8-membered ring.
  • the compound of formula (VIII) can be prepared according to the procedure as reported in WO2019123195.
  • the present invention provides a compound of formula (VIII) or a salt thereof, wherein R 6 is C 1 -C 4 -alkyl.
  • R 6 is C 1 -C 4 -alkyl.
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl and C 3 -C 4 -cycloalkyl; and R 6 is C 1 -C 3 -alkyl.
  • Yet another embodiment of the present invention provides a compound of formula (II) or a salt thereof, wherein R a and R b are independently selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 3 - C 6 -cycloalkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -halocycloalkyl and C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl.
  • Yet another embodiment of the present invention provides a compound of formula (I) or a salt thereof, wherein R 1 , R a and R b , R 2 and R 3 are as defined above.
  • the present invention provides a process for preparing bicyclic anthranilic diamides of the formula (Ia) or a salt thereof, wherein, R 1 is selected from the group consisting of methyl, trifluromethyl, or halogen; R a is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-, iso- or tert-butyl; and R b is selected from the group consisting of hydrogen or methyl; comprising the steps of: a) reacting an acetonitrile (CH 3 CH 2 -CN) of formula (Xa) with a phosphorochloridate of formula (XIa) or a salt thereof, in the presence of a suitable base, a suitable reagent and a suitable solvent, to obtain a diethyl (R 1 substituted) cyanomethylphosphonate of formula (IXa) or a salt thereof; wherein R 1 is as defined herein above;
  • R 1 , R a and R b are as defined herein above; f) coupling the compound of formula (Va) or a salt thereof, with a compound of formula (IVa) or a salt thereof, in the presence of a suitable coupling reagent, a suitable base and a suitable solvent, to obtain a compound of formula (IIIa) or a salt there of wherein R 1 is as defined herein above and; g) amidating the compound of formula (IIIa) or a salt thereof, with a suitable amine [(CH 3 ) 2 CH- NH 2 ] of formula (IIa), to obtain a compound of formula (Ia) or a salt thereof.
  • R 1 , R a and R b are as defined herein above; optionally, h) coupling the compound of formula (XIIa) or a salt thereof, wherein R 1 , R a and R b are as defined herein above; with a compound of formula (IVa) or a salt thereof, in the presence of a suitable reagent, a suitable base and a suitable solvent, to obtain a compound of formula (Ia) or a salt there of; wherein R 1 , R a and R b are as defined herein above;.
  • the reaction step (a) of the above described process for the preparation of anthranilic diamides of formula (I) or a salt thereof can be performed at a temperature ranging from -100 °C to 100 °C for a period of few minutes to several hours, optionally under an inert atmosphere to afford a compound of formula (IX).
  • the reaction temperature ranges from - 80 °C to 40 °C for a period of few minutes to 24 hours under an inert atmosphere.
  • the process is performed in the presence of a base selected from organic, inorganic or organometallics bases.
  • the inorganic base is selected from alkali metal hydroxide for example lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide; alkaline earth metal hydroxides for example, calcium hydroxide, barium hydroxide, magnesium hydroxide; alkali carbonate for example lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; alkaline earth carbonate for example magnesium carbonate, calcium carbonate, barium carbonate; alkali hydride for example lithium hydride, sodium hydride, potassium hydride; alkaline hydride for example magnesium hydride, calcium hydride, barium hydride; metal phosphates for example sodium diphosphate, sodium phosphate, potassium diphosphate, potassium phosphate and the like.
  • alkali metal hydroxide for example lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide
  • alkaline earth metal hydroxides for example, calcium hydroxide, barium hydroxide, magnesium hydroxide
  • alkali carbonate for
  • the organic base is selected from amines which includes but is not limited to ethylamine, triethylamine, isopropylamine diisopropylamine, triisopropylamine, pyridine, piperidine, N,N- (dimethylamino)pyridine (DMAP), tetramethylammonium hydroxide, tetrabutylammonium hydroxide, choline hydroxide; amidine base for example, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, (TBD), 2,3,4,6,7,8,9,10-octahydropyrimidol[1,2-a]azepine (DBU), 1,8-diazabicyclo(5.4.0)undec-7-ene, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) or triethylenediamine).
  • the organometallic base is selected from metal alkoxide which include but is not limited to lithium alkoxide, for example, lithium methoxide, lithium ethoxide, lithium isopropoxide; sodium alkoxide for example, sodium methoxide, sodium ethoxide, sodium isopropoxide; potassium alkoxide, for example potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide; magnesium alkoxide, for example, magnesium ethoxide, magnesium tert-butoxide, magnesium isopropoxide; aluminium alkoxide, for example, aluminium ethoxide, aluminum isopropoxide; titanium alkoxide, for example, titanium(IV) ethoxide titanium(IV) isopropoxide and the like or a mixture thereof.
  • metal alkoxide which include but is not limited to lithium alkoxide, for example, lithium methoxide, lithium ethoxide, lithium isopropoxide; sodium alk
  • Suitable solvents for carrying out the process according to the present invention are all inert organic solvents. These preferably include aliphatic, alicyclic or aromatic hydrocarbons such as, for example, petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2- dimethoxyethane, 1,2-diethoxyethane or anisole; ketones, such as acetone, butanone, methyl
  • reaction step (a) is performed in the presence of a suitable reagent selected from organolithium compounds, preferably the reagent is alkyllithium such as n-butyllithium and as suitable organic base such as diisopropylamine.
  • a suitable reagent selected from organolithium compounds, preferably the reagent is alkyllithium such as n-butyllithium and as suitable organic base such as diisopropylamine.
  • the reaction step (a) is performed in a solvent selected from aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; ethers such as diethyl ether, diisopropyl ether, methyl tert -butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxyethane, 1,2- diethoxyethane, cyclopentylmethylether or anisole; amides such as N,N- dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, N,N′- dimethylpropyleneurea or hexamethyl
  • the reaction step (a) of the above described process can be performed at a temperature ranging from -100 °C to 50 °C for a period of few minutes to several hours, In one embodiment, the reaction step (a) is performed under atmospheric pressure, but can also be carried out under increased or reduced pressure. In one embodiment, after completion of the reaction, the reaction step (a) can be continued to the next step (b) with or without isolation of the intermediate product of formula (IX).
  • the suitable base for performing the reaction step (b) is selected from the suitable bases as provided above. Preferably, the suitable base is selected from alkali carbonate, alkali hydride, amidine, organic amine, or a mixture thereof.
  • the base is selected from alkali carbonate, amidine or organic amines; such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, 2,3,4,6,7,8,9,10-octahydropyrimidol[1,2-a]azepine (DBU), 1,8- diazabicyclo(5.4.0)undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO), ethylamine, triethylamine, isopropylamine diisopropylamine, triisopropylamine, pyridine, piperidine, N,N-(dimethylamino)pyridine (DMAP) or a mixture thereof.
  • DBU 2,3,4,6,7,8,9,10-octahydropyrimidol[1,2-a]azepine
  • DBN 1,8- diazabicyclo(
  • the suitable solvent for performing the reaction step (b) is selected from the suitable solvents as provided for the reaction step above.
  • the suitable solvent is selected from ethers, nitriles, amides, sulfoxides or a mixture thereof.
  • the solvent is selected from ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; ketones, such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles, such as acetonitrile, propionitrile, n- or i- butyronitrile or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N- methylformanilide, N-methylpyrrolidone, N,N′-Dimethylpropyleneurea or hexamethylphosphoramide; esters such as methyl acetate or ethyl acetate; sulphoxides,
  • the reaction step (b) of the above described process can be performed at a temperature ranging from -25 °C to 150 °C for a period of few minutes to several hours, Preferably, the reaction temperature ranges from 0 °C to 100 °C for a period of few minutes to 36 hours.
  • the reaction step (b) is performed under atmospheric pressure, but can also be carried out under increased or reduced pressure.
  • the reaction step (b) can be continue to the next step (c) with or without isolation of the intermediate product of formula (VII).
  • the reaction step (b) can be continue to the next step (d) with or without isolation of the intermediate of formula (VII) and (VI).
  • the base for performing the reaction step (c) is selected from the suitable bases as provided above.
  • the suitable base is selected alkali carbonate for example lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; alkaline earth carbonate for example magnesium carbonate, calcium carbonate, barium carbonate; alkali hydride for example lithium hydride, sodium hydride, potassium hydride; alkaline hydride for example magnesium hydride, calcium hydride, barium hydride; metal phosphates for example sodium diphosphate, sodium phosphate, potassium diphosphate, potassium phosphate and the like; metal alkoxide which include but is not limited to lithium alkoxide, for example, lithium methoxide, lithium ethoxide, lithium isopropoxide; sodium alkoxide for example, sodium methoxide, sodium ethoxide, sodium isopropoxide; potassium alkoxide, for example potassium methoxide,
  • the suitable base is selected from metal carbonate, metal alkoxide, such potassium tert-butoxide or a mixture thereof.
  • the solvent for carrying out the reaction step (c) is selected from the suitable solvents as provided above.
  • the suitable solvent is selected from ethers, nitriles, amides, sulfoxides or a mixture thereof.
  • the solvent is selected from ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2- dimethoxyethane, 1,2-diethoxyethane or anisole; ketones, such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N- methylpyrrolidone, N,N′-dimethylpropyleneurea or hexamethylphosphoramide; esters such as methyl acetate or ethyl acetate; sulphoxides,
  • the reaction step (c) of the above described process can be performed at a temperature ranging from -50 °C to 150 °C for a period of few minutes to several hours, optionally under inert atmosphere to afford a compound of formula (VI).
  • the reaction temperature ranges from -25 °C to 100 °C for a period of few minutes to 24 hours.
  • the reaction step (c) is performed under atmospheric pressure, but can also be carried out under increased or reduced pressure.
  • the reaction step (c) can be continued to the next step (d) with or without isolation of the intermediate product of formula (VI).
  • the compound of formula (VI) is optionally isolated.
  • the reaction step (d) is performed in the presence of a suitable hydrolysing reagent selected from metal hydroxide, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide; metal carbonate, for example lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, barium carbonate; metal alkoxides, for example lithium methoxide, lithium ethoxide, lithium isopropoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert- butoxide, magnesium ethoxide, magnesium tert-butoxide, magnesium isopropoxide, aluminium ethoxide, aluminum isopropoxide; titanium(IV) ethoxide titanium(IV) isopropoxide or a mixture thereof.
  • metal hydroxide for example,
  • the suitable hydrolysing agent is selected from metal hydroxides, metal carbonate or a mixture thereof. More preferably, the suitable hydrolysing agent is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or a mixture thereof.
  • the suitable solvent for carrying out the reaction step (d) is selected from suitable solvents as provided above. Preferably, the suitable solvent is selected from alcohol, ethers, nitriles or a mixture thereof.
  • the suitable solvent is selected from diisopropyl ether, methyl t- butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane; alcohols such as methanol, ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol, ethanediol, propane- 1,2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, water or mixtures thereof.
  • the reaction step (d) of the above described process can be performed at a temperature ranging from -20 °C to 100 °C for a period of few minutes to several hours, optionally under inert atmosphere to afford compound of formula (V).
  • the reaction temperature ranges from -20 °C to 75 °C for a period of few minutes to 24 hours.
  • the reaction step (d) is performed under atmospheric pressure, but can also be carried out under increased or reduced pressure.
  • the reaction step (d) can be continued to the next step (e) with or without isolation of the intermediate product of formula (V).
  • the reaction steps are performed in presence of a suitable base selected from organic amine bases for example, ethylamine, triethylamine, isopropylamine diisopropylamine, triisopropylamine, pyridine, 3-methylpyridine, piperidine, N,N-(dimethylamino)pyridine (DMAP); amidine for example, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, (TBD), 2,3,4,6,7,8,9,10- octahydropyrimidol[1,2-a]azepine (DBU) 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO, triethylenediamine) or a mixture thereof or the inorganic base is selected from alkali carbonate for example lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate;
  • a suitable base selected from organic amine bases
  • the suitable base is selected from amine base and alkali carbonate; more preferably, the suitable base is selected from triethylamine, diisopropylamine, 3-methylpyridine, pyridine, piperidine, lithium carbonate, sodium carbonate, potassium carbonate or a mixture thereof.
  • the reaction could also be performed without additional base.
  • the solvent for carrying out the reaction steps is selected from the suitable solvents as provided above.
  • the suitable solvent is usually selected from ethers, nitriles, ketones, halogenated hydrocarbons, amides or a mixture thereof.
  • the suitable solvent is selected from ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; ketones, such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; halogenated hydrocarbons such as, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; or a mixture thereof.
  • ethers such as diethyl ether, diisopropyl ether, methyl t-butyl
  • reaction steps (e, f or h) are performed under atmospheric pressure, but can also be carried out under increased or reduced pressure.
  • the reaction steps (e, f or h) can be performed at a temperature ranging from 0 °C to 150 °C for a period of few minutes to several hours.
  • the reaction temperature ranges from 0 °C to 75 °C for a period of few minutes to 24 hours.
  • the suitable reagent for steps include but are not limited to oxalyl chloride, sulphonyl chloride, for example thionyl chloride, methanesulphonyl chloride, benzenesulfonyl chloride; carbodiimides, for example N,N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC); aminium compounds, for example (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin
  • the suitable reagent is selected from sulphonyl chloride, carbodiimides or mixture thereof. More preferably, the suitable reagent is selected from sulphonyl chloride such as oxalyl chloride or methanesulphonyl chloride.
  • the reaction step (f) can be continued to the next step (g) with or without isolation of the intermediate product of formula (III).
  • the solvent used for carrying out the reaction step (g) is selected from suitable solvents as provided above.
  • the suitable solvent is selected from ethers, nitriles, amides, sulfoxides or a mixture thereof.
  • the suitable solvent is selected from ether, nitriles, amides or a mixture thereof.
  • the reaction can also be carried out in the absence of a solvent.
  • the reaction step (g) of the above described process can be performed at a temperature ranging from 0 °C to 150 °C for a period of few minutes to several hours, optionally under inert atmosphere to afford the compound of formula (I).
  • the reaction temperature ranges from 0 °C to 100 °C for a period of few minutes to 24 hours.
  • the reaction step (g) is performed under atmospheric pressure, but can also be carried out under increased or reduced pressure.
  • the processes as disclosed in the present invention are preferably carried out batch-wise.
  • reaction passages e.g., under flow conditions
  • the processes as disclosed in the present invention can be carried out in the absence of a suitable solvent or in the presence of one or more suitable solvent.
  • the optional suitable solvent should be resistant against oxidation (i.e. a solvent will be preferred whose rate of oxidation is substantially lower than that of the compounds of formula I to XI) and suitable for suspending, or preferably dissolving the reactants.
  • the isolation of the reaction product can be carried out by a technique which includes but is not limited to decantation, centrifugation, evaporation, liquid-liquid extraction, distillation, recrystallization, chromatography and the like or a combination thereof.
  • the process steps according to the invention are generally carried out under atmospheric pressure. Alternatively, however, it is also possible to work under or increased pressure.
  • the reaction time is not critical and depends on the batch size, temperature, reagent and solvent employed. Typically, the reaction time may vary from a few minutes to several hours. Any person skilled in the art knows the best work-up of the reaction mixtures after the end of the respective reactions. In one embodiment, the work-up is usually carried out by isolation of the product, and optionally washing with suitable solvent, and further optionally drying of the product if useful or required.
  • the isolation of the reaction product can be carried out by a technique which includes but is not limited to decantation, filtration, centrifugation, evaporation, liquid-liquid extraction, distillation, recrystallization, chromatography and the like or a combination thereof.
  • the process steps according to the invention are generally carried out under atmospheric pressure. Alternatively, however, it is also possible to work under reduced pressure or under pressure.
  • reaction mixture was stirred for 30 min at -78°C, then allowed to warm up to 0 °C and further stirred for 30 min. Then, a solution of propionitrile (Xa, 2.02 mL, 29.0 mmol) in tetrahydrofuran (20 mL) was charged at -78 °C, and the resulting mixture was stirred for 15 min. A solution of diethyl phosphorochloridate (XIa, 4.20 mL, 29.0 mmol) in tetrahydrofuran (10 mL) was added slowly to this reaction mixture which was stirred for 45 min at -78°C. The reaction mixture was allowed to warm up to 25 °C and further stirred for 15 min.
  • Xa diethyl phosphorochloridate
  • reaction mixture was diluted in saturated aq. ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain ethyl 2-(5-(2-cyanoprop-1-en-1-yl)-1H-pyrazol-1-yl)acetate (VIIa, 1.0 g, 4.56 mmol, 83% yield) as an off white solid.
  • reaction mixture was stirred for 1.5 h at -20 °C to -10°C. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (250 mL) and quenched with saturated aqueous ammonium chloride solution (250 mL). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (2 x 250 mL). The combined organic layers were washed with water (250 mL), brine solution (250 mL) and concentrated to afford ethyl 6-amino-5- methylpyrazolo[1,5-a]pyridine-7-carboxylate (VIa, 92 g, 420 mmol, 92% yield) as a light green oil.
  • reaction mixture was slowly warmed to 25 °C and stirred for 2.5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (1.5 L), pH was adjusted to 4-5 by using 40% aq. solution of citric acid. The obtained precipitate was stirred for further 1 h and filtered. The wet cake which was obtained was washed with water (200 mL) and dried under reduced pressure to afford 6-amino-5-methylpyrazolo[1,5-a]pyridine- 7-carboxylic acid (Va, 100 g, 523 mmol, 89% yield) as an off white solid.
  • Va 6-amino-5-methylpyrazolo[1,5-a]pyridine- 7-carboxylic acid
  • reaction mixture was stirred for 12 h at 25 °C. After completion of the reaction, the reaction mixture was diluted with water (50 mL), the aqueous layer was separated and pH was adjusted to 4-5 using 20% aq. citric acid solution. The obtained precipitate was stirred further for 30 min and filtered. The resulting wet cake was washed with water (5 mL) and dried under reduced pressure to afford 6-amino-5-methylpyrazolo[1,5-a]pyridine-7-carboxylic acid (Va, 7.6 g, 39.8 mmol, 92% yield) as an off white solid.
  • reaction mixture was slowly warmed to 25 °C and stirred further for 16 h. After completion of the reaction, the reaction mixture was filtered. Potassium tert-butoxide (17.55 g, 156.0 mmol) was added to the filtrate portion wise at 0-3 °C. The reaction mixture was then stirred for 60 min at 4-10 °C. After completion of the reaction, the reaction mixture was diluted with water (100 mL) followed by the addition of aq.2M NaOH solution (52.1 mL, 104.0 mmol) at 5 °C and continued to stir further for 16 h at 25 °C. The reaction mixture was diluted with water (50 mL), aqueous layer was separated and pH was adjusted to 4-5 using 20% aq.
  • the reaction mixture was stirred for 1 h at a temperature between 4 °C to 10 °C. After completion of the reaction, water (250 mL) and aq. 2M NaOH solution (90 mL, 181.0 mmol) were added at 5 °C. The reaction mixture was stirred further for 16 h at 25°C and then diluted with water (150 mL). Aqueous layer was separated and pH was adjusted to 4-5 using 20% aq. citric acid solution. The precipitate obtained was stirred for further 1 h and then filtered.
  • reaction mixture was diluted with water (2000 mL) and stirred for 30 min.
  • the resulting slurry mass was filtered and the solid cake was washed with water and dried under reduced pressure to afford 7-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-5-methyl-9H- pyrazolo[1',5':1,6]pyrido[3,2-d][1,3]oxazin-9-one (IIIa, 320 g, 699 mmol, 89% yield) as a light green solid.
  • reaction mixture was diluted with water (10 mL) and stirred for 30 min.
  • the resulting slurry mass was filtered to obtained a solid cake, which was washed with water and dried under reduced pressure to obtain 7-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-5-methyl-9H- pyrazolo[1',5':1,6]pyrido[3,2-d][1,3]oxazin-9-one (IIIa, 0.9 g, 1.966 mmol, 75% yield) as a light green solid.
  • reaction mixture was allowed to warm up to 25 °C and stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water (4 L) and stirred for 1 h. The resulting slurry mass was filtered to obtain a solid cake, which was washed with water (0.5 L) and dried under reduced pressure to afford 6-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-N-isopropyl-5- methylpyrazolo[1,5-a]pyridine-7-carboxamide (Ia, 600 g, 1161 mmol, 90% yield) as an off white solid.
  • reaction mixture was allowed to warm up to 25 °C and stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (2 x 500 mL). The organic layer was concentrated to obtain a residue, which was subjected to a solution of acetonitrile (400 mL) in water (1600 mL), which was stirred for 1 h at 25 °C.

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PCT/IB2022/055939 2021-06-28 2022-06-27 A process for the preparation of pyrazolopyridine-diamides of formula (i) and intermediates thereof WO2023275705A1 (en)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2019123195A1 (en) 2017-12-20 2019-06-27 Pi Industries Ltd. Pyrazolopyridine-diamides, their use as insecticide and processes for preparing the same.
WO2020170178A1 (en) * 2019-02-22 2020-08-27 Pi Industries Ltd. A process for the synthesis anthranilic diamide compounds and intermediates thereof
WO2021010492A1 (en) * 2019-07-17 2021-01-21 Ono Pharmaceutical Co., Ltd. Compound having kdm5 inhibitory activity and pharmaceutical use thereof
WO2022023931A1 (en) * 2020-07-27 2022-02-03 Pi Industries Ltd A pesticidally active mixture comprising pyrazolopyridine anthranilamide compound, oxides or salts thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019123195A1 (en) 2017-12-20 2019-06-27 Pi Industries Ltd. Pyrazolopyridine-diamides, their use as insecticide and processes for preparing the same.
WO2020170178A1 (en) * 2019-02-22 2020-08-27 Pi Industries Ltd. A process for the synthesis anthranilic diamide compounds and intermediates thereof
WO2021010492A1 (en) * 2019-07-17 2021-01-21 Ono Pharmaceutical Co., Ltd. Compound having kdm5 inhibitory activity and pharmaceutical use thereof
WO2022023931A1 (en) * 2020-07-27 2022-02-03 Pi Industries Ltd A pesticidally active mixture comprising pyrazolopyridine anthranilamide compound, oxides or salts thereof

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