WO2025078273A1

WO2025078273A1 - Process

Info

Publication number: WO2025078273A1
Application number: PCT/EP2024/077915
Authority: WO
Inventors: Imants KREITUSS
Original assignee: Syngenta Crop Protection AG Switzerland
Current assignee: Syngenta Crop Protection AG Switzerland
Priority date: 2023-10-11
Filing date: 2024-10-04
Publication date: 2025-04-17
Anticipated expiration: 2026-04-11

Abstract

A process for the preparation of a compound of Formula (I) where R¹ is selected from one or more of alkyl, substituted alkyl, haloalkyl, cyanoalkyl, alkoxy, halogen, haloalkoxy, amino, aminoalkyl, alkylsulfonyl, arylsulfonyl, alkylsulfanyl, and hydroxy, where n is selected from 1, 2, or 3, comprising the reaction of a compound of Formula (II) with 2-haloheptafluoropropane, in the presence of sodium dithionite (Na₂S₂O₄) and an aqueous buffer, where the aqueous buffer comprises an acid and a base.

Description

Process

The present invention relates to a novel process for the preparation of perfluoroaryl compounds and their use as intermediates in the preparation of agrochemicals.

Carbon-carbon bonding forming reactions for perfluoroaryl compounds in the presence of sodium dithionate are known in the art, see for example, 'Hernandez, et al., The Journal of Organic Chemistry, 2021 86 (15), 10903-10913'. However, such reactions are time-consuming, inconsistent in terms of their results and extremely difficult to scale up into a commercially viable process.

In particular, the process described in the art is associated with an initiation period, pH swings, particularly at the start of the process in the reaction chamber, and overreduction of the fluorine- containing reagent to the corresponding environmentally persistent hydrofluoro compound.

The present invention addresses at least these technical challenges and hereby provides a process for the preparation of a compound of Formula I:

Formula I where R¹ is selected from one or more of alkyl, substituted alkyl, haloalkyl, cyanoalkyl, alkoxy, halogen, haloalkoxy, amino, aminoalkyl, alkylsulfonyl, arylsulfonyl, alkylsulfanyl, and hydroxy, where n is selected from 1, 2, or 3, comprising the reaction of a compound of Formula II:

Formula II with 2-haloheptafluoropropane, in the presence of sodium dithionite (NajSjCU) and an aqueous buffer, where the aqueous buffer comprises an acid and a base.

This process has surprisingly been found to be robust, inexpensive, non-toxic, reproducible and environmentally favourable. The high water solubility of the buffer system also improves product isolation.

Preferably, R¹ is selected from one or more of Ci-salkyl, Ci-shaloalkyl, Ci-salkoxy, chlorine, fluorine, iodine, Ci-shaloalkoxy, amino, aminoCi-salkyl, arylsulfonyl, Ci-salkylsulfanyl, and hydroxy.

Preferably, when 'n' is greater than 1 R¹ is selected from amino and one or more of alkyl, substituted alkyl, haloalkyl, cyanoalkyl, alkoxy, halogen, haloalkoxy, aminoalkyl, alkylsulfonyl, arylsulfonyl, alkylsulfanyl, and hydroxy.

More preferably, when 'n' is greater than 1 R¹ is selected from amino and one or more of Ci.aalkyl, Ci- shaloalkyl, Ci.aalkoxy, chlorine, fluorine, iodine, Ci-shaloalkoxy, aminoCi-salkyl, arylsulfonyl, Ci- salkylsulfanyl, and hydroxy.

As used herein, the term "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

As used herein, the term "hydroxyl" or "hydroxy" means an -OH group.

As used herein, the term "hydrosulfido" or "mercapto" means an -SH group.

As used herein, the term "cyano" means a -CN group.

As used herein, amino means an -NH2 group.

As used herein, acyl means a -C(O)CH3 group.

As used herein, formyl means a -C(O)H group.

As used herein, oxo means an =0 group (eg, as in a carbonyl (C=0) group).

As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and which is attached to the rest of the molecule by a single bond. The term "Cl-3alkyl" is to be construed accordingly. Examples of Cl- 6alkyl include, but are not limited to, methyl, ethyl, n-propyl, and the isomers thereof, for example, iso-propyl. A "alkylene" group refers to the corresponding definition of alkyl, except that such radical is attached to the rest of the molecule by two single bonds. The term "Cl-2alkylene" is to be construed accordingly. Examples of Cl-3alkylene, include, but are not limited to, -CH2-, -CH2CH2- and -(CH2)3-.

As used herein, the term " haloalkyl" refers to a alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. Cl-3haloalkyl is to be construed accordingly. Examples of Cl-3haloalkyl include, but are not limited to fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.

As used herein, the term "cyanoalkyl" refers to an alkyl radical as generally defined above substituted by one or more cyano groups. CyanoCl-3alkyl is to be construed accordingly. Examples of cyanoCl- 3alkyl include, but are not limited to, cyanomethyl.

As used herein, the term "alkoxy" refers to a radical of the formula -ORa wherein Ra is an alkyl radical as generally defined above. Cl-3alkoxy is to be construed accordingly. Examples of Cl-3alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, and iso-propoxy.

As used herein, the term "haloalkoxy" refers to an alkoxy group as defined above substituted by one or more of the same or different halogen atoms. Cl-3haloalkoxy is to be construed accordingly. Examples of Cl-3haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, fluoroethoxy, trifluoromethoxy, and trifluoroethoxy.

As used herein, the term "aminoalkyl" refers to a radical of the formula H2NRa- wherein Ra is an alkylene radical as generally defined above.

As used herein, the term "alkylsulfonyl" refers to a radical of the formula -S(O)2Ra wherein Ra is an alkyl radical as generally defined above. The term "Cl-3alkylsulfonyl" is to be construed accordingly. The term "arylsulfonyl" is as above but where Ra is an optional substituted aryl group.

As used herein, the term "alkylsulfanyl" refers to a radical of the formula -SRa wherein Ra is an alkyl radical as generally defined above. The term "Cl-3alkylsulfanyl" is to be construed accordingly.

The process as described herein has been found to be remarkably robust to the extent that Formula II may added in 'crude' form, i.e., less than 100% by weight purity. Compound of Formula II may be added as a composition containing from 70 to 99% by weight of Formula II. By "weak acid" we mean an acid that has a pKa of greater than or equal to 1, such from 1 to 7.

Preferably the weak acid is selected from citric acid, acetic acid, lactic acid, methyl maleic acid, tartaric acid, phosphoric acid and/or formic acid. Most preferred are citric acid and/or acetic acid.

Advantageously, the 2-haloheptafluoropropane is 2-iodoheptafluoropropane.

The ratio of 2-iodoheptafluoropropane to Formula II may be from 0.8:1 to 2:1, preferably from 0.9:1 to 1.8:1, or even from 0.95:1 to 1.7:1. Using 2-iodoheptafluoropropane as the limiting agent allows to minimize the environmentally persistent perfluoro side products. This is particularly advantageous in reactions with aniline derivatives where unreacted starting material can be readily separated from the product via an acid-base wash and afterwards recycled.

The process is preferably carried out at a pH of from 3 to 5, more preferably from a pH of 4 to 4.5.

The base may be hydroxide. Advantageously, the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium acetate, and/or ammonium formate.

The aqueous buffer may be prepared comprising the steps of (1) the dissolution of the weak acid in water, and (2) the subsequent addition of an aqueous base solution until a pH of from 3 to 5 is reached.

The process may be carried out in the presence of an alcoholic solvent (e.g., tert-amyl alcohol) an ether solvent (e.g., methyl tert-butyl ether) or an ester solvent, preferably ethyl acetate, isopropylacetate, or butyl acetate, most preferably ethyl acetate.

The 2-haloheptafluoropropane may be added in an ester solution as defined above.

Advantageously the process comprises the addition of sodium carbonate (NajCOs) in order to control the pH of the reaction. The sodium carbonate may be added in parallel with the addition of sodium dithionate.

The process may further comprise a phase transfer catalyst (PTC). Preferred PTCs include tetraalkylammonium salts such as tetrabutylammonium hydrogen sulphate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethyl ammonium chloride, tetraethyl ammonium bromide, tetramethyl ammonium chloride and tetramethyl ammonium bromide. Tetraethyl ammonium chloride is the most preferred PTC for the process.

The reaction is preferably carried out at a reaction temperature of from 25 to 50 °C, most preferably from 30 to 40 °C.

In an embodiment:

(1) the compound of Formula II and 2-haloheptafluoropropane are combined in the reaction vessel,

(2) the vessel is heated to the reaction temperature, and

(3) sodium dithionite solution is dosed at a rate such that the reaction temperature is not exceeded.

The process may further comprise recycling any unreacted compound of Formula II back into the reaction chamber. Such a recycling step allows an excess of Formula II to be used in the process.

Advantageously, the salts associated with the buffer may be removed upon phase separation and an aqueous wash.

The process described herein may be used for the production of an agrochemical.

There is also provided a compound of Formula I produced by a process as defined herein.

Unless otherwise stated all percentages are given as percentages by total weight and all embodiments and preferred features may be combined in any combination.

The invention is described by the following non-limiting Examples.

Examples

The following reaction scheme (Reaction 1) was carried out as set out below.

Reaction 1

Example 1

Preparation of buffer

Citric acid (192 g, 1 mol) was dissolved in 500 g of water. The pH was adjusted to pH = 4.3 by adding 50% aqueous NaOH (142.5 g, 1.8 mol) to the citric acid solution. The pH was measured with a pH sensor.

Preparation of sodium dithionite solution

Aqueous sodium carbonate (21wt%, 6.2g, 12 mmol, 0.2 equiv) was added to 30g of water under nitrogen. To this solution was added 7.1 g sodium dithionite (85%, 35 mmol, 0.56 equiv) to afford a solution with pH = 9.1.

Reaction

Equipment: 350 mL multi-neck reactor equipped with an overhead stirrer, pH sensor, internal thermometer, 2 addition funnels (one funnel is filled with aqueous sodium dithionite solution the other with 21% aqueous sodium carbonate solution), gas scrubber filled with 5% aqueous NaOH and nitrogen inlet.

Difluoromethoxy aniline (10.0 g, 63 mmol, 1.0 equiv) was dissolved in EtOAc (45 mL). To this solution under stirring and a gentle flow of nitrogen was added tetraethylammonium chloride (0.1 g, 0.6 mmol, 0.01 equiv), citric acid/sodium citrate buffer (20 g) (prepared as described above) and 10 g of water.

This biphasic mixture is heated to T = 30 °C before 2-iodoheptafluoropropane (25 g, 84 mmol, 1.3 equiv) is dosed over 15 min. To the reaction mixture sodium dithionite solution (prepared as described above) and 21% aqueous sodium carbonate solutions are added dropwise in parallel over 2 - 2.5 hours while maintaining the pH = 4.2 - 4.6.

After full addition of sodium dithionite solution reaction is stirred at T = 30 °C for an additional hour and aqueous sodium carbonate is added to maintain pH = 4.2 - 4.6.

Results

Upon completion as analysed by GC the reaction is cooled down to room temperature. Phases are separated (aqueous phase at the bottom) and organic phase is washed 2 x 25 g of water (aqueous phase at the top - phase inversion). Solvent is removed under reduced pressure through rotary evaporator to afford product as an orange liquid (18.3 g, 90% yield - mass loss due to sampling during reaction) at 95% strength.

¹H, NMR (400 MHz, CDCb) 8 ppm: 7.30 (m, 2H), 6.85 (m, 1 H), 6.51 (t, J = 73.6 Hz (H-C-F), 1 H), 4.12 (br.s. 2H)

The identity and yield of the product as 2-difluoromethoxy-4-heptafluoroaniline was confirmed by ¹H QNMR .

Example 2

Procedure with 2-iodoheptafluoropropane as limiting reagent

To a multi-neck reactor equipped with overhead stirrer, internal pH probe, thermometer, reflux condenser and 2 separate inlets for addition (addition funnel or dosage pump) is added crude 2- difluoromethoxy aniline (82 wt%) (70 g, 0.36 mol, 1.0 equiv) followed by EtOAc (280 mL), tetraethyl ammonium chloride (0.4 g, 3.0 mmol, 1 mol%) and citric acid buffer (140 g).

Heptafluoroisopropyl iodide (104 g, 0.35 mol, 0.95 equiv) is added to the reaction mixture sub-level. During this addition slightly exothermic event is observable (rises from T = 22 °C to T = 24 °C). Once all components have been combined the reaction mass is heated to T = 30 °C. Once T = 30 °C is reached sodium dithionite is dosed over the course of 2.5 - 3 h. In order to maintain the required process 4.1 < pH < 4.6 a 21 wt% aqueous solution of NajCOs is dosed in parallel (gas evolution observable with the base dosage). The progress of the reaction is monitored by GC.

Upon completion vacuum (300 mbar) is applied for 1 h to remove the side product heptafluoropropane. The reaction mixture is then cooled to room temperature, phases are separated and the organic phase is washed 2 x 70g water and 1 x 70g 20wt% sulfuric acid to remove the unreacted aniline. The organic phase is then neutralized to pH = 7 - 8 by addition of 2wt% NaOH. The phases are then separated and solvent is removed under reduced pressure to afford the product as a brown-dark orange liquid (106 g in ~80% quality by ^TH QNMR with solvent EtOAc as the main impurity).

The successful use of heptafluoroisopropyl iodide as the limiting reagent has environmental benefits and the excess compounds of Formula II can be recycled back into the process.

The invention is defined by the claims.

Claims

1. A process for the preparation of a compound of Formula I:

2. A process according to claim 1, wherein R¹ is selected from one or more of Ci.aalkyl, Ci- shaloalkyl, Ci.aalkoxy, chlorine, fluorine, iodine, Ci-shaloalkoxy, amino, aminoCi-salkyl, arylsulfonyl, Ci-salkylsulfanyl, and hydroxy.

3. A process according to claim 1 or 2, wherein 2-haloheptafluoropropane is 2- iodoheptafluoropropane.

4. A process according to any of the preceding claims, wherein the process is carried out at a pH of from 3 to 5, preferably from a pH of 4 to 4.5.

5. A process according to any of the preceding claims, wherein the acid is a weak acid, preferably selected from citric acid, acetic acid, lactic acid, methyl maleic acid, tartaric acid, phosphoric acid and/or formic acid.

6. A process according to any of the preceding claims, wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium acetate, ammonium formate.

7. A process according to any of the preceding claims, wherein the ratio of 2- haloheptafluoropropane to Formula II is from 0.8:1 to 2:1.

8. A process according to any of the preceding claims, wherein the process is carried out in the presence of an alcoholic, ether, or an ester solvent, preferably an ester solvent.

9. A process according to any of the preceding claims further comprising the addition of sodium carbonate (NajCOs).

10. A process according to any of the preceding claims further comprising a phase transfer catalyst (PTC).

11. A process according to any of the preceding claims, wherein the reaction is carried out at a reaction temperature of from 25 to 50 °C, preferably from 30 to 40 °C.

12. A process according to claim 11, wherein the compound of Formula II and 2- haloheptafluoropropane are combined in the reaction vessel; the vessel is heated to the reaction temperature; and sodium dithionite solution is dosed at a rate such that the reaction temperature is not exceeded.

13. A process according to any of the preceding claims, further comprising recycling any unreacted compound of Formula II back into the reaction chamber.

14. A process for producing an agrochemical, comprising any of the preceding claims.

15. A compound of Formula I produced by a process according to any of claims 1 to 14.