EP4695229A1 - Process for the preparation of 2-(pyrid-2-yloxymethyl) phenylacetates - Google Patents

Process for the preparation of 2-(pyrid-2-yloxymethyl) phenylacetates

Info

Publication number
EP4695229A1
EP4695229A1 EP24723366.1A EP24723366A EP4695229A1 EP 4695229 A1 EP4695229 A1 EP 4695229A1 EP 24723366 A EP24723366 A EP 24723366A EP 4695229 A1 EP4695229 A1 EP 4695229A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
solvent
phenyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24723366.1A
Other languages
German (de)
French (fr)
Inventor
James J. HENKELIS
Nicholas M. Irvine
Mark ONDARI
Rafael Shapiro
Eric WIENSCH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Corteva Agriscience LLC
Original Assignee
Corteva Agriscience LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Corteva Agriscience LLC filed Critical Corteva Agriscience LLC
Publication of EP4695229A1 publication Critical patent/EP4695229A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • Compounds of formula (I) are useful as agricultural chemicals, useful for the control of pests and diseases.
  • Another approach to synthesizing picoxystrobin involves the reaction of enol-ether compound (8) with a metal salt of 2-hydroxy-6-trifluoromethylpyridine (7), where M is Na or K.
  • a useful compound of formula (I) is (E -Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acrylate.
  • methods described herein provide a highly efficient route to (E -Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acrylate.
  • compounds R-L and R'-L' represent carbon-containing groups R and R' attached to leaving groups L and L 1 .
  • a carbon-containing group R or R' is Ci to C4, branched or unbranched, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, or haloalkynyl.
  • Preferred R groups are Ci to C4 alkyl, branched or unbranched.
  • a leaving group L or L' may be halogen as in methyl iodide or methyl bromide or methyl chloride or methyl fluoride; sulfate as in dimethyl sulfate or other dialkyl sulfate; halosulfonate as in methyl fluorosulfonate or methyl chlorosulfonate other alkyl halosulfonate; alkyl sulfonate as in methyl methanesulfonate or other alkyl alkyl sulfonate; haloalkylsulfonate as in methyl trifluoromethanesulfonate or other alkyl haloalkylsulfonate; phenyl sulfonate or substituted-phenylsulfonate as in methyl benzenesulfonate, methyl p- toluenesulfonate, methyl p-brominesulfonate or other alkyl phenyl
  • a metal suitable for making alkoxides and carboxylates is a metal such as lithium, sodium, potassium, rubidium, cesium, beryllium, magnesium, calcium, strontium, barium, copper, zinc, silver, cadmium, gold, mercury, titanium, or other alkali, or alkaline earth, or transition metal.
  • a metal such as lithium, sodium, potassium, rubidium, cesium, beryllium, magnesium, calcium, strontium, barium, copper, zinc, silver, cadmium, gold, mercury, titanium, or other alkali, or alkaline earth, or transition metal.
  • ranges such as temperature ranges and time-period ranges include the starting and ending points.
  • a temperature range of from 0 °C to 10 °C includes the temperatures of 0 °C and 10 °C.
  • a time-period of from 1 to 4 hours includes the time periods of 1 hour and four hours.
  • THF tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • DMF dimethylformamide
  • DMS dimethyl sulfate
  • FA formic acid
  • MTBE methyl tertiary -butyl ether
  • a “solution” refers to a compound or multiple compounds mixed with a solvent, or a compound or multiple compounds mixed with a liquid reagent such as methyl formate.
  • a “phase transfer catalyst” may be a crown ether, azacrown, thiacrown, phosphonium salt, or a quaternary ammonium salt.
  • exemplary quaternary ammonium salts include benzyltrimethyl ammonium chloride, benzyltrimethyl ammonium bromide, benzyltrimethyl ammonium hydroxide, benzyltrimethyl ammonium hydrosulfide, benzyltri ethyl ammonium chloride, benzyltriethyl ammonium bromide, benzyltriethyl ammonium hydroxide, benzyltriethyl ammonium hydrosulfide, benzyltripropyl ammonium chloride, benzyltripropyl ammonium bromide, benzyltripropyl ammonium hydroxide, benzyltripropyl ammonium hydrosulfide, benzyltributyl
  • Preferred quaternary ammonium salts include tetrabutyl ammonium chloride, tetrabutyl ammonium hydrogen sulfate, tetrabutyl ammonium bromide, tetrabutyl ammonium hydroxide and other tetrabutyl ammonium salts.
  • a “one-pot synthesis”, or “one-pot reaction sequence”, or “one-pot method” is a method in which all the steps of the process are performed in a single reaction vessel without removing and purifying intermediate compounds of the process. Compared to multi-pot syntheses, one-pot syntheses may save time and resources while increasing final product yield.
  • continuous-flow methods or systems refers to methods and systems wherein the steps of a process or reaction sequence are performed in an apparatus through which solvent and reactants flow continuously while the individual steps of the process or method are executed.
  • Multi-step continuous-flow systems act as several reactors connected into a single sequential flow. Generally, reagents are pumped into such systems at appropriate locations to execute the desired reactions.
  • Exemplary methods for preparing compounds of formula (II) wherein Z is halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxy carbonyl, or alkylcarbonyloxy; and Y n wherein n 0, 1, 2, or 3 is independently halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxycarbonyl, or alkylcarbonyloxy; and R is Ci to C4, branched or unbranched, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, or haloalkynyl; may comprise: a) reacting a 2-fluoropyridine of formula (IV) in a solvent;
  • An exemplary method for preparing a compound of formula (II) may comprise the steps being performed with a solvent selected from the group consisting of water, acetonitrile, DMF, THF, toluene, and mixtures thereof.
  • An exemplary method for preparing a compound of formula (II) may comprise the use of the solvent toluene.
  • An exemplary method for preparing a compound of formula (II) may be employed wherein a solution of 3-isochromanone and 2-trifluoro-6-trifluoromethylpyridine are added to sodium hydroxide in a solvent.
  • An exemplary method for preparing a compound of formula (II) may comprise the steps being performed in one pot.
  • An exemplary method for preparing a compound of formula (II) may comprise the steps being performed in a continuous flow system.
  • An exemplary method of preparing a compound of structure (I) wherein Z is halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxycarbonyl, or alkylcarbonyloxy; and wherein Y n is independently halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxycarbonyl, or alkylcarbonyloxy and n 0 to 3; and wherein R and R' are Ci to C4, branched or unbranched, alkyl, alkenyl, alkynyl, haloalkyl, haloalkeny
  • An exemplary method for the synthesis of a compound of formula (I) may comprise the steps being performed with a solvent selected from the group consisting of water, acetonitrile, DMF, THF, toluene, and mixtures thereof.
  • An exemplary method for the synthesis of a compound of formula (I) may comprise the solvent toluene.
  • An exemplary method for the synthesis of a compound of formula (I) may comprise 3- isochromanone being reacted with sodium hydroxide in a solvent to produce a compound of formula (III) to which is added a solution of 2-fluoro-6-trifluoromethylpyridine.
  • An exemplary method for the synthesis of a compound of formula may comprise a solution of 3- isochromanone and 2-trifluoro-6-trifluoromethylpyridine being added to sodium hydroxide in a solvent.
  • An exemplary method for the synthesis of a compound of formula (I) may comprise the steps being performed in one pot.
  • An exemplary method for the synthesis of a compound of formula (I) may comprise the steps being performed in a continuous flow system.
  • An exemplary method may comprise a final methylation reaction to form a compound of formula (I) employing a phase transfer catalyst.
  • An exemplary method may comprise the use of a phase transfer catalyst selected from the group consisting of tetrabutylammonium hydroxide, tetrabutyl ammonium hydrogen sulfate, tetrabutylammonium chloride, and tetrabutylammonium bromide.
  • a phase transfer catalyst selected from the group consisting of tetrabutylammonium hydroxide, tetrabutyl ammonium hydrogen sulfate, tetrabutylammonium chloride, and tetrabutylammonium bromide.
  • An exemplary method may comprise the final product being purified by recrystallization.
  • An exemplary reaction sequence may begin by reacting 3-isochromanone with alkaline base.
  • 3-Isochromanone may be treated with 2 to 2.5 equivalents of base in solvent. After mixing base and 3-isochromanone, the reaction mixture may be stirred for 30 minutes to 24 hours. Upon completion of the reaction, water - if present - may be removed under vacuum at temperatures from 25 °C to 50 °C, with or without the aid of an azeotroping solvent.
  • Suitable bases including lithium hydroxide, sodium hydroxide, potassium hydroxide, or mixtures thereof may be employed.
  • Suitable solvents include water, DMF, DMSO, cyclohexanone, and THF/water mixtures. Temperatures from 25 °C to 75 °C may be employed.
  • Reaction temperatures from 45 °C to 55 °C, from 50 °C to 60 °C, from 55 °C to 65 °C, from 60 °C to 70 °C, from 65 °C to 75 °C, from 70 °C to 80 °C from 75 °C to 85 °C, and from 80 °C to 90 °C may be used.
  • the reaction mixture may then be cooled to between 0 °C and 10 °C. Temperatures from 0 °C to 5 °C, from 5 °C to 10 °C, and from 10 °C to 15 °C may be used.
  • the intermediate carboxylate salt may be formed by adding a solution of 3-isochromanone and 2-fluoro-6-trifluoromethylpyridine to a solvent/alkaline-base mixture.
  • a base such as potassium carbonate
  • solvent may then be added to the reaction mixture.
  • Suitable solvents include DMF, cyclohexanone, toluene, MTBE, THF and DMSO.
  • Base addition may be followed by dropwise addition of R-L, such as dimethyl sulfate, while maintaining a reaction temperature between 0 °C and 10 °C. Temperatures from 0 °C to 5 °C, from 5 °C to 10 °C, 0 °C and 15 °C and from 10 °C to 15 °C may be used.
  • the reaction mixture may then be warmed to a temperature of from 25 °C to 90 °C and stirred for a period of from 30 minutes to 4 hours to yield the product (2). Exemplary yields are as shown in Table 1.
  • the temperature may be allowed to warm to a temperature of from 20 °C to 35 °C, preferably from 25 °C to 30 °C, and stirred from 1 to 5 hours, preferably from 2.5 to 3.5 hours.
  • the reaction may then be cooled to a temperature of from 0 °C to 5 °C.
  • a mixture of E- and Z-enols and aldehyde may be dissolved in anhydrous solvent.
  • Suitable solvents include DMF, DMSO, acetonitrile, MTBE, and toluene.
  • the solution may be cooled to a temperature of from 0 °C to 15 °C, preferably to a temperature of from 0 °C to 10 °C, followed by addition of base, such as potassium carbonate.
  • An alkylating agent R'-L 1 such as dimethyl sulfate, may then be added to the reaction mixture while maintaining a temperature of from 0 °C to 15 °C, preferably from 0 °C to 10 °C.
  • the yield of the entire reaction sequence is in the range of from about 80% to about 90%.
  • water-sensitive reagents are employed under an anhydrous nitrogen atmosphere, and anhydrous solvents are employed unless otherwise specified.
  • the 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetic acid obtained from the previous reaction was cooled to a temperature of from 0 °C to 10 °C, then K2CO3 (18.66 g) was added in one portion.
  • Dimethyl sulfate (14.1 mL) was added dropwise while maintaining a reaction temperature of from 0 °C to 10 °C. Upon completion of the dimethyl sulfate addition, the reaction mixture was warmed to a temperature of from 20 °C to 30 °C.
  • the mixture was cooled to a temperature of from about 0 °C to about 5 °C.
  • a dilute HC1 solution (2.5 equiv.) was added to the mixture, while maintaining the temperature within a range of from about 0 °C to about 15.0 °C, until a pH of from about 3.5 to about 5 was observed.
  • the mixture was extracted with MTBE and the solvent was removed under vacuum to provide the product methyl 2-(2-(((6- (trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate as a mixture of E and Z isomers as well as aldehyde.
  • the anhydrous products of the previous reaction including 3-hydroxy-2-(2-(((6- (trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acrylate, (-80.0 g) were dissolved in acetonitrile (392 g). Potassium carbonate (57.0 g) was added and the mixture was stirred and warmed to a temperature of from about 45 °C to about 55 °C. Dimethyl sulfate 23 g was added and the mixture was stirred for a period of from about 2 to about 5 hours. Water (92.0 g) was added and the mixture was stirred for a period of from about 30 minutes to about 2 hours.
  • reaction mixture was stirred at 25 °C and reaction progress was monitored by HPLC.
  • the reaction mixture was cooled to 0 °C and 125 g of saturated HC1 solution (44.9%) in methanol was added.
  • the reaction mixture was stirred for 30 minutes at 15 °C.
  • Deionized water 510.26 g, 63.19 eq was added.
  • the mixture was stirred for 30 min. at 15 °C and the mixture was allowed to settle for 30 minutes.
  • the organic and aqueous phases were separated.
  • the organic layer (739 g) contained the formylated intermediate methyl 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate as a mixture of E and Z enols and aldehyde. The mixture was used in subsequent steps. In situ phase transfer catalyst formation
  • Tributylamine (2.77 g 0.015 mol; 0.1 mol eq relative to methyl 2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acetate) and 26.26 g of DMS (Purity: 99.7%, 1.39 eq with respect to methyl 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate) were added simultaneously over 15 min at 0-5 °C.
  • LCMS was performed with a HALO 90 A C18, 2.7 n m, 4.6 *30mm column, at a temperature of 45 °C.
  • Two eluent phases (A, B) were employed: A: 99.5% water, 0.05% formic acid; B: 99.5% acetonitrile, 0.05% formic acid.
  • the elution profile is shown in the Table below:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

Described herein are processes for the preparation of 2-(pyrid-2-yloxymethyl)-phenylacetates which are useful as intermediates for agricultural products. The processes comprise reacting a substituted pyridine with phenylacetic acid alcohol dianions derived from 3-isochromanone. The intermediates may be further reacted to form agricultural products such as fungicides.

Description

PROCESS FOR THE PREPARATION OF 2-(PYRID-2-YLOXYMETHYL) PHENYLACETATES
Cross Reference to Related Application
This application claims priority to U.S. Patent Application Ser. No. 63/496177 filed April 14, 2023, the contents of which are hereby incorporated herein by reference.
Background
Compounds of formula (I) are useful as agricultural chemicals, useful for the control of pests and diseases.
One such compound, picoxystrobin, /E/-Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acrylate, compound (1), is shown below.
Picoxystrobin (1)
Picoxystrobin is a broad-spectrum fungicide used against a variety of diseases in wheat, barley, and rye.
General strategies for synthesizing picoxystrobin include treating methyl 2-(6-trifluoromethyl-2- yl oxy m ethyl )phenyl acetate (2) with methyl formate followed by methylation of the enol ether intermediate with dimethyl sulfate (DMS). The same chemistry may be employed in the synthesis of related strobilurin compounds. Other suitable procedures are described in US2004/0152894. Routes for the synthesis of compound (2) are discussed in US 5942623 and US 6015905.
According to US 5942623, a disodium salt of 2-hydroxymethylphenylacetic acid (compound 3, M = Na) was reacted with 2-chloro-6-trifluoromethylpyridine (compound 4, L = Cl) in N- methylpyrrolidone. Upon completion of the reaction dimethyl sulfate was added to form the product (2). Other metals M and leaving groups L may be employed in its process.
According to US 6015905, a sodium salt of 2-hydroxy-6-trifluoromethylpyridine (compound 7, M = Na) was reacted with methyl 2-chloromethylphenylacetate (compound 6, L = Cl). Other metals (M) and leaving groups (L) may be employed in its reaction.
A variety of conditions were tested, and reported yields ranged from 51% to 97%.
Another approach to synthesizing picoxystrobin involves the reaction of enol-ether compound (8) with a metal salt of 2-hydroxy-6-trifluoromethylpyridine (7), where M is Na or K.
Despite the large amount of work devoted to the synthesis of picoxystrobin and related strobilurin compounds, there remains a continuing need for improved syntheses that address problems of cost, waste, and stereochemical control of the enol-ether double bond. Description
Surprisingly, it has been found that reacting a 2-fluoropyridine with the dilithium, disodium, or dipotassium salt of 3-isochromanone followed by esterification results in an unexpectedly high yield of compounds of formula (II), which may then be converted to useful agricultural chemicals, such as compounds of formula (I). A useful compound of formula (I) is (E -Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acrylate. In particular, methods described herein provide a highly efficient route to (E -Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acrylate.
As described herein, compounds R-L and R'-L' represent carbon-containing groups R and R' attached to leaving groups L and L1. A carbon-containing group R or R' is Ci to C4, branched or unbranched, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, or haloalkynyl. Preferred R groups are Ci to C4 alkyl, branched or unbranched. A leaving group L or L' may be halogen as in methyl iodide or methyl bromide or methyl chloride or methyl fluoride; sulfate as in dimethyl sulfate or other dialkyl sulfate; halosulfonate as in methyl fluorosulfonate or methyl chlorosulfonate other alkyl halosulfonate; alkyl sulfonate as in methyl methanesulfonate or other alkyl alkyl sulfonate; haloalkylsulfonate as in methyl trifluoromethanesulfonate or other alkyl haloalkylsulfonate; phenyl sulfonate or substituted-phenylsulfonate as in methyl benzenesulfonate, methyl p- toluenesulfonate, methyl p-brominesulfonate or other alkyl phenyl sulfonate or alkyl substituted- phenylsulfonate.
As used herein, a metal suitable for making alkoxides and carboxylates is a metal such as lithium, sodium, potassium, rubidium, cesium, beryllium, magnesium, calcium, strontium, barium, copper, zinc, silver, cadmium, gold, mercury, titanium, or other alkali, or alkaline earth, or transition metal. As described herein, all reactions involving water-sensitive or oxygen-sensitive reagents are performed under a dry nitrogen atmosphere. All solvents involving water-sensitive or oxygensensitive reagents are anhydrous.
As used herein, ranges such as temperature ranges and time-period ranges include the starting and ending points. For example, a temperature range of from 0 °C to 10 °C includes the temperatures of 0 °C and 10 °C. Likewise, a time-period of from 1 to 4 hours includes the time periods of 1 hour and four hours.
As used herein, “THF” is tetrahydrofuran, “DMSO” is dimethyl sulfoxide, “DMF” is dimethylformamide, “DMS” is dimethyl sulfate, “FA” is formic acid, “MTBE” is methyl tertiary -butyl ether.
As used herein, a “solution” refers to a compound or multiple compounds mixed with a solvent, or a compound or multiple compounds mixed with a liquid reagent such as methyl formate.
As used herein, a “phase transfer catalyst” (PTC) may be a crown ether, azacrown, thiacrown, phosphonium salt, or a quaternary ammonium salt. Exemplary quaternary ammonium salts include benzyltrimethyl ammonium chloride, benzyltrimethyl ammonium bromide, benzyltrimethyl ammonium hydroxide, benzyltrimethyl ammonium hydrosulfide, benzyltri ethyl ammonium chloride, benzyltriethyl ammonium bromide, benzyltriethyl ammonium hydroxide, benzyltriethyl ammonium hydrosulfide, benzyltripropyl ammonium chloride, benzyltripropyl ammonium bromide, benzyltripropyl ammonium hydroxide, benzyltripropyl ammonium hydrosulfide, benzyltributyl ammonium chloride, benzyltributyl ammonium bromide, benzyltributyl ammonium hydroxide, benzyltributyl ammonium hydrosulfide, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium hydroxide, tetrabutyl ammonium hydrosulfide, trioctylmethyl ammonium chloride, trioctylmethyl ammonium bromide, trioctylmethyl ammonium hydroxide, and trioctylmethyl ammonium hydroxide. Preferred quaternary ammonium salts include tetrabutyl ammonium chloride, tetrabutyl ammonium hydrogen sulfate, tetrabutyl ammonium bromide, tetrabutyl ammonium hydroxide and other tetrabutyl ammonium salts.
As used herein, a “one-pot synthesis”, or “one-pot reaction sequence”, or “one-pot method” is a method in which all the steps of the process are performed in a single reaction vessel without removing and purifying intermediate compounds of the process. Compared to multi-pot syntheses, one-pot syntheses may save time and resources while increasing final product yield.
As used herein, “continuous-flow methods or systems”, refers to methods and systems wherein the steps of a process or reaction sequence are performed in an apparatus through which solvent and reactants flow continuously while the individual steps of the process or method are executed. Multi-step continuous-flow systems act as several reactors connected into a single sequential flow. Generally, reagents are pumped into such systems at appropriate locations to execute the desired reactions.
Exemplary methods for preparing compounds of formula (II) wherein Z is halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxy carbonyl, or alkylcarbonyloxy; and Yn wherein n = 0, 1, 2, or 3 is independently halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxycarbonyl, or alkylcarbonyloxy; and R is Ci to C4, branched or unbranched, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, or haloalkynyl; may comprise: a) reacting a 2-fluoropyridine of formula (IV) in a solvent; with a compound of formula (III) wherein M is lithium, sodium, potassium, or any other metal suitable for making alkoxides and carboxylates; to obtain a compound of formula (V); and b) reacting (V) with a compound of formula R-L, wherein R is Ci to C4, branched or unbranched, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, or haloalkynyl; and L is fluoro, chloro, bromo, iodo, sulfate, fluorosulfonate, alkylsulfonate, phenyl sulfonate, substituted phenyl sulfonate or the equivalent; to obtain a compound of formula (II).
An exemplary method for preparing a compound of formula (II) may comprise n = 0, Z = CF3, and R = CH3.
An exemplary method for preparing a compound of formula (II) may comprise M = Na and R-L = dimethyl sulfate.
An exemplary method for preparing a compound of formula (II) may comprise the steps being performed with a solvent selected from the group consisting of water, acetonitrile, DMF, THF, toluene, and mixtures thereof.
An exemplary method for preparing a compound of formula (II) may comprise the use of the solvent toluene.
An exemplary method for preparing a compound of formula (II) may comprise 3-isochromanone reacting with sodium hydroxide in a solvent to produce a compound of formula (III M = Na) to which is then added a solution of 2-fluoro-6-trifluoromethylpyridine.
An exemplary method for preparing a compound of formula (II) may be employed wherein a solution of 3-isochromanone and 2-trifluoro-6-trifluoromethylpyridine are added to sodium hydroxide in a solvent.
An exemplary method for preparing a compound of formula (II) may comprise the steps being performed in one pot.
An exemplary method for preparing a compound of formula (II) may comprise the steps being performed in a continuous flow system. An exemplary method of preparing a compound of structure (I) wherein Z is halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxycarbonyl, or alkylcarbonyloxy; and wherein Yn is independently halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxycarbonyl, or alkylcarbonyloxy and n = 0 to 3; and wherein R and R' are Ci to C4, branched or unbranched, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, or haloalkynyl; may comprise: a) reacting a 2-fluoropyridine of formula (IV) in a solvent; with a compound of formula (III) wherein M is lithium, sodium, potassium, or any other metal suitable for making alkoxides and carboxylates; to obtain a compound of formula (V); and b) alkylating a compound of formula (V) with a compound of formula R-L, wherein L is fluoro, chloro, bromo, iodo, sulfate, fluorosulfonate, alkyl sulfonate, phenyl sulfonate, substituted phenyl sulfonate or the equivalent; to obtain a compound of formula (II); and c) reacting a compound of formula (II) with an alkyl formate to form a mixture of compounds of formula (IX); and d) alkylating the mixture of compounds of formula (IX) with a compound of formula R'-L', wherein L' is fluoro, chloro, bromo, iodo, sulfate, fluorosulfonate, alkyl sulfonate, phenyl sulfonate, substituted phenylsulfonate or the equivalent; to form a compound of formula (I).
An exemplary method for the synthesis of a compound of formula (I) may comprise n = 0, Z = CF3, R = CH3, and R' = CH3.
An exemplary method for the synthesis of a compound of formula (I) may comprise M = Na, R'-L' = dimethyl sulfate, and R-L = dimethyl sulfate.
An exemplary method for the synthesis of a compound of formula (I) may comprise the steps being performed with a solvent selected from the group consisting of water, acetonitrile, DMF, THF, toluene, and mixtures thereof.
An exemplary method for the synthesis of a compound of formula (I) may comprise the solvent toluene.
An exemplary method for the synthesis of a compound of formula (I) may comprise 3- isochromanone being reacted with sodium hydroxide in a solvent to produce a compound of formula (III) to which is added a solution of 2-fluoro-6-trifluoromethylpyridine. An exemplary method for the synthesis of a compound of formula may comprise a solution of 3- isochromanone and 2-trifluoro-6-trifluoromethylpyridine being added to sodium hydroxide in a solvent.
An exemplary method for the synthesis of a compound of formula (I) may comprise the steps being performed in one pot.
An exemplary method for the synthesis of a compound of formula (I) may comprise the steps being performed in a continuous flow system.
An exemplary method may comprise a final methylation reaction to form a compound of formula (I) employing a phase transfer catalyst.
An exemplary method may comprise the use of a phase transfer catalyst selected from the group consisting of tetrabutylammonium hydroxide, tetrabutyl ammonium hydrogen sulfate, tetrabutylammonium chloride, and tetrabutylammonium bromide.
An exemplary method may comprise the final product being purified by recrystallization.
An exemplary reaction sequence may begin by reacting 3-isochromanone with alkaline base.
Table 1
3-Isochromanone may be treated with 2 to 2.5 equivalents of base in solvent. After mixing base and 3-isochromanone, the reaction mixture may be stirred for 30 minutes to 24 hours. Upon completion of the reaction, water - if present - may be removed under vacuum at temperatures from 25 °C to 50 °C, with or without the aid of an azeotroping solvent.
Suitable bases including lithium hydroxide, sodium hydroxide, potassium hydroxide, or mixtures thereof may be employed. Suitable solvents include water, DMF, DMSO, cyclohexanone, and THF/water mixtures. Temperatures from 25 °C to 75 °C may be employed.
To the anhydrous product of the previous reaction under a nitrogen atmosphere may be added anhydrous solvent followed by dropwise addition of 1 to 1.1 equivalents of a 2-halopyridine, for example 2-chloro-6-trifluoromethylpyridine. Suitable solvents include THF, DMF, MTBE, DMSO, cyclohexanone, and toluene. The reaction mixture may be stirred for from 5 to 32 hours at from 45 °C to 90 °C. Reaction temperatures from 45 °C to 55 °C, from 50 °C to 60 °C, from 55 °C to 65 °C, from 60 °C to 70 °C, from 65 °C to 75 °C, from 70 °C to 80 °C from 75 °C to 85 °C, and from 80 °C to 90 °C may be used. The reaction mixture may then be cooled to between 0 °C and 10 °C. Temperatures from 0 °C to 5 °C, from 5 °C to 10 °C, and from 10 °C to 15 °C may be used. Alternatively, the intermediate carboxylate salt may be formed by adding a solution of 3-isochromanone and 2-fluoro-6-trifluoromethylpyridine to a solvent/alkaline-base mixture.
A base, such as potassium carbonate, and solvent may then be added to the reaction mixture. Suitable solvents include DMF, cyclohexanone, toluene, MTBE, THF and DMSO. Base addition may be followed by dropwise addition of R-L, such as dimethyl sulfate, while maintaining a reaction temperature between 0 °C and 10 °C. Temperatures from 0 °C to 5 °C, from 5 °C to 10 °C, 0 °C and 15 °C and from 10 °C to 15 °C may be used. The reaction mixture may then be warmed to a temperature of from 25 °C to 90 °C and stirred for a period of from 30 minutes to 4 hours to yield the product (2). Exemplary yields are as shown in Table 1.
Table 2
TBAHS = tetrabutylammonium hydrogen sulfate; TBAC = tetrabutylammonium chloride
An enol ether may be added to a compound of formula (II) as follows. A compound of formula (II), such as the anhydrous compound of formula (2), may be dissolved in a formate ester, such as methyl formate under a nitrogen atmosphere at a temperature of from 20 °C to 35 °C, preferably from 25 °C to 30 °C followed by cooling to a temperature of from 0 °C to 5 °C. A solution of sodium methoxide in methanol may be added dropwise while maintaining a temperature of from 0 °C to 5 °C. The temperature may be allowed to warm to a temperature of from 20 °C to 35 °C, preferably from 25 °C to 30 °C, and stirred from 1 to 5 hours, preferably from 2.5 to 3.5 hours. The reaction may then be cooled to a temperature of from 0 °C to 5 °C. Aqueous hydrochloric acid may then be added while maintaining the reaction temperature in a range of from 0 °C and 5 °C. Acid addition may be stopped when the pH of the reaction mixture is between pH = 3 and pH = 4. An aldehyde/E-enol/Z-enol mixture is obtained.
A mixture of E- and Z-enols and aldehyde may be dissolved in anhydrous solvent. Suitable solvents include DMF, DMSO, acetonitrile, MTBE, and toluene. The solution may be cooled to a temperature of from 0 °C to 15 °C, preferably to a temperature of from 0 °C to 10 °C, followed by addition of base, such as potassium carbonate. An alkylating agent R'-L1, such as dimethyl sulfate, may then be added to the reaction mixture while maintaining a temperature of from 0 °C to 15 °C, preferably from 0 °C to 10 °C. Upon completion of alkylating agent addition, the reaction may be warmed to a temperature of from 20 °C to 35 °C, preferably from 20 °C to 25 °C. The mixture may then be stirred for an hour. A phase transfer catalyst may optionally be employed in the alkylation reaction. Suitable phase transfer catalysts include tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium hydrogen sulfate. Excess alkylating agent may be removed with an aqueous alkaline base, such as potassium hydroxide solution, followed by extraction to isolate the product, such as a compound of formula (I). The product may be purified by recrystallization. In the case of the compound of formula (1), recrystallization may be performed with ethyl acetate/heptane.
The yield of the entire reaction sequence is in the range of from about 80% to about 90%.
Experimental
In the following experimental examples, water-sensitive reagents are employed under an anhydrous nitrogen atmosphere, and anhydrous solvents are employed unless otherwise specified.
Synthesis of sodium 2-(2-(hydroxymethyl)phenyl)acetate
To a solution of 3-isochromanone (20.0 g) in THF (200 mL) was added NaOH (12.1 g) with stirring at RT (25 °C). After 5 minutes, water (5.5mL, 304 mmol) was added dropwise. After stirring for 30 minutes, solvent was removed in vacuo to provide a white solid. To this solid was added THF (2 x) followed by solvent removal in vacuo (2 x) to yield a light grey solid, sodium 2-(2-(hydroxymethyl)phenyl)acetate.
Sodium 2-(2-(hydroxymethyl)phenyl)acetate: 'H N.MR (400 MHz, D2O) 5 7.48 - 7.21 (m, 4H), 4.66 (s, 2H), 3.64 (s, 2H). LCMS: [M+l] =189. (la) was used directly in the next step.
Synthesis of 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetic acid
To sodium 2-(2-(hydroxymethyl)phenyl)acetate was added anhydrous THF (200 mL) forming a suspension, then 2-fluoro-6-trifluoromethylpyridine (22.5 g) was added with and stirred at a temperature of from 20 °C to 30 °C. The reaction mixture was heated to a temperature of from 45 °C to 55 °C for a period of from 8 to 16 hours to yield 2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acetic acid. LCMS indicated a minor amount of 2-hydroxy-6- trifluoromethylpyridine was formed.
(2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetic acid): [HNMR (400 MHz, DMSO-d6) 8 12.35 (s, 1H), 7.97 (t, J = 7.9 Hz, 1H), 7.49 (d, J = 7.1 Hz, 2H), 7.29 (dt, J = 4.8, 3.5 Hz, 3H), 7.13 (d, J = 8.4 Hz, 1H), 5.38 (s, 2H), 3.73 (s, 2H). 13C NMR (101 MHz, DMSO- d6) 5 172.95 (s, 1C), 163.39 (s, 1C), 144.13 (q, J = 34.1 Hz, 1C), 141.40 (s, 1C), 135.40 (s, 1C), 135.00 (s, 1C), 131.45 (s, 1C), 130.32 (s, 1C), 128.80 (s, 1C), 127.35 (s, 1C), 121.84 (q, J = 273.7 Hz, 1C), 115.86 (s, 1C), 114.52 (d, J = 3.2 Hz, 1C), 66.34 (s, 1C), 38.55 (s, 1C). 19F NMR (376 MHz, DMSO) 8 -66.90 (s, 3F). LCMS: [M+l]= 312, [M+23]= 334
2-hydroxy-6-trifluoromethylpyridine: 1H NMR (400 MHz, DMSO-d6) 8 11.72 (s, 1H), 7.95 - 7.82 (m, 1H), 7.32 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) 8 164.47 (s, 1C), 144.41 (q, J = 33.7 Hz, 1C), 141.41 (s, 1C), 121.87 (q, J = 273.8 Hz, 1C), 114.70 (s, 1C), 112.54 (d, J = 2.9 Hz, 1C). 19F NMR (376 MHz, DMSO) 8 -66.90 (s, 3F). LCMS: [M+l]= 164
Synthesis of methyl 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate
The 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetic acid obtained from the previous reaction was cooled to a temperature of from 0 °C to 10 °C, then K2CO3 (18.66 g) was added in one portion. Dimethyl sulfate (14.1 mL) was added dropwise while maintaining a reaction temperature of from 0 °C to 10 °C. Upon completion of the dimethyl sulfate addition, the reaction mixture was warmed to a temperature of from 20 °C to 30 °C. After 2 hours, the reaction mixture was cooled to a temperature of from 0 °C to 10 °C and quenched with 200 mL 0.1 mol/L KOH, the aqueous layer was extracted with 200 mL EtOAc, the combined organic layers were washed with brine. The organic phase was dried over Na SO4 and concentrated to yield 42 g of methyl 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate.
Methyl 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate: 'H NMR (400 MHz, DMSO-d6) 8 7.98 (t, J = 7.8 Hz, 1H), 7.59 - 7.43 (m, 2H), 7.38 - 7.24 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 5.38 (s, 2H), 3.84 (s, 2H), 3.57 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 8 171.83 (s, 1C), 163.34 (s, 1C), 144.19 (q, J = 34.2 Hz, 1C), 141.38 (s, 1C), 135.41 (s, 1C), 134.39 (s, 1C), 131.51 (s, 1C), 130.51 (s, 1C), 128.91 (s, 1C), 127.56 (s, 1C), 121.83 (q, J = 273.7 Hz, 1C), 115.72 (s, 1C), 114.46 (d, J = 3.2 Hz, 1C), 66.32 (s, 1C), 52.02 (s, 1C), 38.11 (s, 1C). 19F NMR (376 MHz, DMSO) 8 -66.85 (s, 3F). LCMS: [M+l]= 326, [M+23]= 348
Anhydrous methyl 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate (54 g) was combined with anhydrous methyl formate (277 g) and the mixture was cooled to a temperature of from about 10 °C to about 20 °C. A solution of sodium methoxide (25 wt.% in MeOH; 273.59 g) was added over a period of from about 30 minutes to about 90 minutes. Upon completion of the addition, the mixture was warmed to a temperature of from about 20 °C to about 30 °C and stirred for a period of from about 1 to about 3 hours. At the end of this time the mixture was cooled to a temperature of from about 0 °C to about 5 °C. A dilute HC1 solution (2.5 equiv.) was added to the mixture, while maintaining the temperature within a range of from about 0 °C to about 15.0 °C, until a pH of from about 3.5 to about 5 was observed. The mixture was extracted with MTBE and the solvent was removed under vacuum to provide the product methyl 2-(2-(((6- (trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate as a mixture of E and Z isomers as well as aldehyde.
Enols: ’H NMR (400 MHz, DMSO) 8 11.02 (s, 1H), 7.95 (t, J = 7.7 Hz, 1H), 7.84 (s, 1H), 7.55 - 7.50 (m, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.16 - 7.11 (m, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.23 (s, 2H), 3.54 (s, 3H). 19F NMR (376 MHz, DMSO) 8 -66.90 (s, 3F). LCMS [M+l] =354, [M+23] =376
Aldehyde: JH NMR (400 MHz, DMSO) 8 9.14 (s, 1H), 8.50 (s, 1H), 7.93 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.15 - 7.07 (m, 3H), 7.05 - 6.99 (m, 1H), 5.20 (s, 2H), 3.39 (d, J = 4.0 Hz, 3H). 19F NMR (376 MHz, DMSO) 8 -67.01 (s, 3F). LCMS [M+l] =354, [M+23] =376
Synthesis of (E)-Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acrylate
The anhydrous products of the previous reaction, including 3-hydroxy-2-(2-(((6- (trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acrylate, (-80.0 g) were dissolved in acetonitrile (392 g). Potassium carbonate (57.0 g) was added and the mixture was stirred and warmed to a temperature of from about 45 °C to about 55 °C. Dimethyl sulfate 23 g was added and the mixture was stirred for a period of from about 2 to about 5 hours. Water (92.0 g) was added and the mixture was stirred for a period of from about 30 minutes to about 2 hours. After analysis indicated completion of the reaction the mixture was cooled to a temperature of from about 15 °C to about 25 °C. The reaction mixture was extracted with MTBE and the solvent was removed in vacuo. The crude product was dried via azeotropic distillation with acetonitrile to yield (TT -Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acrylate, a yellow oil.
Crystallization of (Ej-Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acrylate
To crude 60 -Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acrylate (7.24g) was added EtOAc (3.6 mL). Then n-heptane (50 mL) was added dropwise with stirring. A white solid gradually precipitated. Upon completion of n- heptane addition, the suspension was cooled to a temperature of from 0 °C to 5 °C. After stirring for a time of from 30 minutes to two hours, the suspension was fdtered and the solid was washed with n-heptane (10 ml x 3). EJ-Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acrylate (5.33 g) was obtained, (purity 98% in HPLC)
(E)-Methyl 3-methoxy-2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acrylate: JH NMR (400 MHz, DMSO) 8 7.96 (t, J = 7.9 Hz, 1H), 7.61 (s, 1H), 7.55 - 7.49 (m, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.18 - 7.10 (m, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.23 (s, 2H), 3.79 (s, 3H), 3.57 (s, 3H). 19F NMR (376 MHz, DMSO) 6 -66.92 (s, 3F). LCMS [M+l] =368, [M+23] =390
Synthesis of Picoxystrobin
To a 2L jacketed reactor, toluene (300 g, 7.26 eq), sodium methoxide (84.90 g, solid, purity: 99.2%, 3.48 eq) and methanol (29.91 g, 2.03 eq) were added at room temperature. A solution of methyl 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate (-384 g, 38.10% in toluene, 1 equiv.) and methyl formate (143.23 g, 97.2% purity, 5.17 eq) was added over a period of 1 hr 45 minutes at room temperature. The reaction mixture was stirred at 25 °C and reaction progress was monitored by HPLC. The reaction mixture was cooled to 0 °C and 125 g of saturated HC1 solution (44.9%) in methanol was added. The reaction mixture was stirred for 30 minutes at 15 °C. Deionized water (510.26 g, 63.19 eq) was added. The mixture was stirred for 30 min. at 15 °C and the mixture was allowed to settle for 30 minutes. The organic and aqueous phases were separated. The organic layer (739 g) contained the formylated intermediate methyl 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate as a mixture of E and Z enols and aldehyde. The mixture was used in subsequent steps. In situ phase transfer catalyst formation
A mixture of methyl 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate (E and Z isomers and aldehyde ~48 g dissolved in toluene; 246 g total) was added to a IL jacketed reactor equipped with an overhead stirrer, reflux condenser, and nitrogen inlet. Tributylamine (2.77 g 0.015 mol; 0.1 mol eq relative to methyl 2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acetate) and 26.26 g of DMS (Purity: 99.7%, 1.39 eq with respect to methyl 2-(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)phenyl)acetate) were added simultaneously over 15 min at 0-5 °C.
To the above reaction mixture was added a 10 wt% solution of KOH in water (210.92 g, 95% purity, 2.37 eq relative to methyl 2-(2-(((6-(trifluoromethyl)pyridin-2- yl)oxy)methyl)phenyl)acetate) at 2-6 °C over 60 min. The reaction mixture was heated to 25 °C and stirred for 2 hours. The reaction progress and the DMS content were monitored by HPLC and GC analysis, respectively. Upon completion, the reaction mixture was allowed to settle for 15 min and the phases were separated. The aqueous layer was further extracted with toluene (84.11 g, 6.10 eq) at 25 °C. The combined organic layers (314 g total) were distilled to remove solvent and crystallized to yield 49.9 g of picoxystrobin (90% yield, 98.3 wt%).
Analytical methods
LCMS was performed with a HALO 90 A C18, 2.7 n m, 4.6 *30mm column, at a temperature of 45 °C. Two eluent phases (A, B) were employed: A: 99.5% water, 0.05% formic acid; B: 99.5% acetonitrile, 0.05% formic acid. The elution profile is shown in the Table below:
Table 3
LCMS Elution method
NMR analysis was performed as follows:
'HNMR: 400MHz, DMSO-d6; 13C NMR: 101MHz, DMSO-d6; 19F NMR: 376MHz, DMSO-d6

Claims

Claims
1. A process for preparing a compound of formula (II) wherein Z is halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxycarbonyl, or alkylcarbonyloxy; and Yn wherein n = 0, 1, 2, or 3 is independently halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxycarbonyl, or alkylcarbonyloxy; and R is Ci to C4, branched or unbranched, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, or haloalkynyl which comprises: a) reacting a 2-fluoropyridine of formula (IV) in a solvent; with a compound of formula (III) wherein M is lithium, sodium, potassium, or any other metal suitable for making alkoxides and carboxylates; to obtain a compound of formula (V); and b) reacting the compound of formula (V) with a compound of formula R-L, wherein L is fluoro, chloro, bromo, iodo, sulfate, fluorosulfonate, alkyl sulfonate, phenyl sulfonate, substituted phenyl sulfonate, or the equivalent, to obtain a compound of formula (II).
2. The process of claim 1 wherein n is 0, Z is CFs, and R is CH3.
3. The process of claim 2 wherein M is Na and R-L is dimethyl sulfate.
4. The process of claim 3 wherein the steps are performed with a solvent selected from the group consisting of water, acetonitrile, DMF, THF, toluene, and mixtures thereof.
5. The process of claim 4 wherein the solvent is toluene.
6. The process of claim 4 wherein 3-isochromanone is reacted with sodium hydroxide in a solvent to produce a compound of formula (III) to which is then added a solution of 2-fluoro-6- tri fluoromethylpyridine.
7. The process of claim 4 wherein a solution of 3-isochromanone and 2-trifluoro-6- trifluoromethylpyridine are added to sodium hydroxide in a solvent.
8. The process of claim 1 wherein the steps are performed in one pot.
9. The process of claim 1 wherein the steps are performed in a continuous flow system.
10. A process for preparing a compound of structure (I) wherein Z is halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxycarbonyl, or alkylcarbonyloxy; and wherein Yn is independently halo, haloalkyl, haloalkoxy, phenyl, phenoxy, amino, alkylamino, dialkylamino, acylamino, cyano, carboxy, alkoxycarbonyl, or alkylcarbonyloxy and n = 0 to 3; and wherein R and R' are the same or different and selected from Ci to C4, branched or unbranched, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, or haloalkynyl; which comprises: a) reacting a 2-fluoropyridine of formula (IV) in a solvent; with a compound of formula (III) wherein M is lithium, sodium, potassium, or any other metal suitable for making alkoxides and carboxylates; to obtain a compound of formula (V); and b) alkylating a compound of formula (V) with a compound of formula R-L, wherein L is fluoro, chloro, bromo, iodo, sulfate, fluorosulfonate, alkyl sulfonate, phenyl sulfonate, substituted phenyl sulfonate or the equivalent; to obtain a compound of formula (II); and c) reacting a compound of formula (II) with an alkyl formate to form a mixture of compounds of formula (IX); and d) alkylating the mixture of compounds of formula (IX) with a compound of formula R'-L' wherein and L' is fluoro, chloro, bromo, iodo, sulfate, fluorosulfonate, alkyl sulfonate, phenyl sulfonate, substituted phenyl sulfonate or the equivalent; to form a compound of formula (I).
11. The process of claim 10 wherein n is 0, Z is CF3, R is CH3, and R' is CH3.
12. The process of claim 11 wherein M is Na, R'-L' is dimethyl sulfate, and R-L is dimethyl sulfate.
13. The process of claim 12 wherein the steps are performed with a solvent selected from the group consisting of water, acetonitrile, DMF, THF, toluene, and mixtures thereof.
14. The process of claim 13 wherein the solvent is toluene.
15. The process of claim 13 wherein 3-isochromanone is reacted with sodium hydroxide in a solvent to produce a compound of formula (III) to which is added a solution of 2-fluoro-6- tri fluoromethylpyridine.
16. The process of claim 13 wherein a solution of 3-isochromanone and 2-trifluoro-6- trifluoromethylpyridine are added to sodium hydroxide in a solvent.
17. The process of claim 10 wherein the steps are performed in one pot.
18. The process of claim 10 wherein the steps are performed in a continuous flow system.
19. The process of claim 13 wherein the final methylation reaction employs a phase transfer catalyst.
20. The process of claim 13 wherein the phase transfer catalyst is formed in situ.
21. The process of claim 13 wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, and tetrabutylammonium bromide.
22. The process of claim 13 wherein the final product is purified by recrystallization.
EP24723366.1A 2023-04-14 2024-04-10 Process for the preparation of 2-(pyrid-2-yloxymethyl) phenylacetates Pending EP4695229A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363496177P 2023-04-14 2023-04-14
PCT/US2024/023849 WO2024215741A1 (en) 2023-04-14 2024-04-10 Process for the preparation of 2-(pyrid-2-yloxymethyl) phenylacetates

Publications (1)

Publication Number Publication Date
EP4695229A1 true EP4695229A1 (en) 2026-02-18

Family

ID=90924951

Family Applications (1)

Application Number Title Priority Date Filing Date
EP24723366.1A Pending EP4695229A1 (en) 2023-04-14 2024-04-10 Process for the preparation of 2-(pyrid-2-yloxymethyl) phenylacetates

Country Status (3)

Country Link
EP (1) EP4695229A1 (en)
CN (1) CN121039103A (en)
WO (1) WO2024215741A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119707798A (en) * 2025-01-03 2025-03-28 大连九信精细化工有限公司 Preparation method of 2, 4-bis [2- (6-trifluoromethyl pyridine-2-oxymethyl) phenyl ] dimethyl glutarate

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9520355D0 (en) 1995-10-05 1995-12-06 Zeneca Ltd Chemical process
WO1997001538A1 (en) 1995-06-28 1997-01-16 Zeneca Limited Process for the preparation of 2-(6-substituted pyrid-2-yloxymethyl)phenylacetate
US20040152894A1 (en) 2001-06-26 2004-08-05 Nippon Soda Co. Ltd Process for producing acrylic acid derivative
CN110467567B (en) * 2018-05-09 2022-11-29 南通泰禾化工股份有限公司 Preparation method of picoxystrobin

Also Published As

Publication number Publication date
WO2024215741A1 (en) 2024-10-17
CN121039103A (en) 2025-11-28

Similar Documents

Publication Publication Date Title
RU2542985C1 (en) Method of obtaining 4-amino-5-fluoro-3-halogen-6-(substituted)picolinates
JP2005537219A (en) Alkenone production
EP3265439B1 (en) Process for preparing 3-chloro-2-vinylphenylsulfonates
EP4695229A1 (en) Process for the preparation of 2-(pyrid-2-yloxymethyl) phenylacetates
CN107428648B (en) Process for the preparation of compounds such as 3-arylbutyraldehyde useful for the synthesis of medetomidine
TW201332944A (en) Process
EP0990647B1 (en) Process for producing quinolone derivatives
JP2771994B2 (en) Method for producing propenoic acid derivative
US20030176721A1 (en) Method for the production of trifluoroethoxy-substituted benzoic acids
WO2021193786A1 (en) 6-(fluoroalkyl)-3,4-dihydro-2h-pyran-5-carboxylic acid ester derivative, method for producing derivative, method for producing 2-(fluoroalkyl)nicotinic acid ester derivative, and method for producing 2-(fluoroalkyl)nicotinic acid derivative
EP1873145B1 (en) Method for producing nicotinic acid derivative or salt thereof
JPH09169733A (en) Production of 4-trifluoromethylnicotinic acid
JP2804559B2 (en) Method for producing 2-chloro-5-chloromethylpyridine
KR20140107364A (en) Method for preparing 2,6-difluoroacetophenones
JP5205971B2 (en) Method for producing tetrahydropyran compound
JP2936741B2 (en) Hydroxyiminoheptanoic acid esters and method for producing the same
JP4030289B2 (en) Process for producing β-ketonitriles
KR20180081276A (en) Method for producing 5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2h)-pyrimidinyl)phenylthiol compounds
JP3918468B2 (en) 3,3-bis (alkoxycarbonyl-methylthio) propionitrile and process for producing the same
IL93228A (en) Process for the preparation of substituted cyclopropane carbaldehydes and intermediate compounds
WO2007090464A1 (en) Process for preparing letrozole
KR100843125B1 (en) Method for preparing beta-ketoester compound
KR20010044286A (en) The manufacturing for method of alkyl-3-(2,6-dehalogen-5-fluorine)-oxo-3- pyridine propionates
JPH1171325A (en) Method for producing alkyl 4-arylbutanoates
JP2000191554A (en) Production of acrylic acid derivative having functional group having high reaction activity

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20251014

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR