Process
By using sodium dithionite and an aqueous buffer solution in the presence of acid and base, the problems of long reaction time and inconsistent products of perfluoroaryl compounds have been solved. This method enables the preparation of perfluoroaryl compounds in a robust, inexpensive, non-toxic, and reproducible manner, improving product separation and reducing environmental pollution.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SYNGENTA CROP PROTECITON AG
- Filing Date
- 2024-10-04
- Publication Date
- 2026-05-08
AI Technical Summary
In the prior art, the carbon-carbon bonding formation reaction of perfluoroaryl compounds is time-consuming, yields inconsistent results, and is difficult to scale up. Furthermore, fluorine-containing reagents are easily over-reduced into environmentally persistent hydrofluoric compounds.
The reaction of compound II with 2-halogenated heptafluoropropane was carried out in the presence of acid and base using sodium dithionite and aqueous buffer solution, with the pH value controlled between 3 and 5. A phase transfer catalyst was used to optimize the reaction conditions to improve robustness and product separation.
A robust, inexpensive, non-toxic, and reproducible method for preparing perfluoroaryl compounds has been developed, which improves product separation and environmental friendliness and reduces persistent environmental byproducts.
Smart Images
Figure CN122003398A_ABST
Abstract
Description
[0001] This invention relates to a novel method for preparing perfluoroaryl compounds, and the use of said perfluoroaryl compounds as intermediates in the preparation of agrochemicals.
[0002] The carbon-carbon bond formation of perfluoroaryl compounds in the presence of sodium dithionate is 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, their results are inconsistent, and scaling up to a commercially viable method is extremely difficult.
[0003] Specifically, the methods described in this art are related to the initiation period, pH changes (especially when the method is started in the reaction chamber), and the excessive reduction of fluorinated reagents to the corresponding environmentally persistent hydrofluoric compounds.
[0004] This invention addresses at least these technical challenges and provides a method for preparing compounds having formula I:
[0005] Formula I
[0006] Where R 1 The group is selected from one or more of the following: alkyl, substituted alkyl, haloalkyl, cyanoalkyl, alkoxy, halogen, haloalkoxy, amino, aminoalkyl, alkylsulfonyl, arylsulfonyl, alkylthioalkyl, and hydroxyl, wherein n is selected from 1, 2, or 3.
[0007] The method includes making a compound having formula II:
[0008] Formula II
[0009] With 2-haloheptafluoropropane,
[0010] The reaction occurs in the presence of sodium dithionite (Na2S2O4) and an aqueous buffer solution.
[0011] The aqueous buffer solution contains both acid and base.
[0012] Surprisingly, this method has been found to be robust, inexpensive, non-toxic, reproducible, and environmentally friendly. The high water solubility of the buffer system also improves product separation.
[0013] Preferably, R 1 Selected from one or more of the following: C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, chlorine, fluorine, iodine, C 1-3 Halogenated alkoxy, amino, amino C 1-3 Alkyl, arylsulfonyl, C 1-3 Alkyl thioalkyl and hydroxyl.
[0014] Preferably, when 'n' is greater than 1, R 1 It is selected from amino and one or more of the following: alkyl, substituted alkyl, haloalkyl, cyanoalkyl, alkoxy, halogen, haloalkoxy, aminoalkyl, alkylsulfonyl, arylsulfonyl, alkylthioalkyl and hydroxy.
[0015] More preferably, when 'n' is greater than 1, R 1 Selected from amino and one or more of the following: C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, chlorine, fluorine, iodine, C 1-3 Halogenated alkoxy groups, amino groups 1-3 Alkyl, arylsulfonyl, C 1-3 Alkyl thioalkyl and hydroxyl.
[0016] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.
[0017] As used herein, the term "hydroxyl" or "hydroxyl" refers to the -OH group.
[0018] As used herein, the terms “hydrothioyl” or “mercaptoyl” refer to the -SH group.
[0019] As used in this article, the term "cyano" refers to the -CN group.
[0020] As used in this article, amino refers to the -NH2 group.
[0021] As used in this article, acyl means -C(O)CH3 group.
[0022] As used in this article, formyl group refers to the -C(O)H group.
[0023] As used herein, oxo means =O group (e.g., as in carbonyl (C=O) groups).
[0024] As used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any unsaturation, and attached to the rest of the molecule by a single bond. The term "C1-3 alkyl" should be interpreted accordingly. Examples of C1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and their isomers, such as isopropyl.
[0025] An "alkylene group" refers to the corresponding definition of an alkyl group, the difference being that this group is attached to the rest of the molecule via two single bonds. The term "C1-2 alkylene" should be interpreted accordingly. Examples of C1-3 alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, and -(CH2)3-.
[0026] As used herein, the term "haloalkyl" refers to an alkyl group as generally defined above, which is substituted with one or more of the same or different halogen atoms. C1-3 haloalkyl should be interpreted accordingly. Examples of C1-3 haloalkyl include, but are not limited to, fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.
[0027] As used herein, the term "cyanoalkyl" refers to an alkyl group as generally defined above, substituted with one or more cyano groups. C1-3 alkyl cyano groups should be interpreted accordingly. Examples of C1-3 alkyl cyano groups include, but are not limited to, cyanomethyl cyano.
[0028] As used herein, the term "alkoxy" refers to a group having the formula -ORa, where Ra is an alkyl group as generally defined above. C1-3 alkoxy groups should be interpreted accordingly. Examples of C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and isopropoxy.
[0029] As used herein, the term "haloalkoxy" refers to an alkoxy group as defined above, which is substituted with one or more of the same or different halogen atoms. C1-3 haloalkoxy groups should be interpreted accordingly. Examples of C1-3 haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, fluoroethoxy, trifluoromethoxy, and trifluoroethoxy.
[0030] As used herein, the term "aminoalkyl" refers to a group having the formula H2NRa-, where Ra is an alkylene group as generally defined above.
[0031] As used herein, the term "alkylsulfonyl" refers to a group having the formula -S(O)₂Ra, where Ra is an alkyl group as generally defined above. The term "C₁-3 alkylsulfonyl" should be interpreted accordingly. The term "arylsulfonyl" is as described above, but where Ra is an optionally substituted aryl group.
[0032] As used herein, the term "alkylthioalkyl" refers to a group having the formula -SRa, where Ra is an alkyl group as generally defined above. The term "C1-3 alkylthioalkyl" should be interpreted accordingly.
[0033] It has been found that the method described herein is very robust to the extent that Formula II can be added in a 'crude' form (i.e., with a purity of less than 100% by weight). Compounds having Formula II can be added as compositions containing 70% to 99% by weight of Formula II.
[0034] The term "weak acid" refers to an acid with a pKa greater than or equal to 1, such as an acid with a pKa of 1 to 7.
[0035] Preferably, the weak acid is selected from citric acid, acetic acid, lactic acid, methylmaleic acid, tartaric acid, phosphoric acid, and / or formic acid. Citric acid and / or acetic acid are most preferred.
[0036] Advantageously, 2-halogenated heptafluoropropane is 2-iodoheptafluoropropane.
[0037] The ratio of 2-iodoheptafluoropropane to Formula II can 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 a limiting agent minimizes persistent perfluorinated byproducts. This is particularly advantageous in reactions with aniline derivatives, where unreacted starting materials can be readily separated from the products via acid-base washing and subsequent recycling.
[0038] The method is preferably carried out at a pH of 3 to 5, more preferably at a pH of 4 to 4.5.
[0039] The base can be a hydroxide. Advantageously, the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium acetate and / or ammonium formate.
[0040] The preparation of an aqueous buffer solution may include the following steps: (1) dissolving a weak acid in water, and (2) subsequently adding an aqueous solution of base until the pH reaches 3 to 5.
[0041] This method can be carried out in the presence of an alcohol solvent (e.g., tert-amyl alcohol), an ether solvent (e.g., methyl tert-butyl ether), or an ester solvent (preferably ethyl acetate, isopropyl acetate, or butyl acetate, most preferably ethyl acetate).
[0042] 2-Hydrohalopyrofluoropropane can be added to ester solutions as defined above.
[0043] Advantageously, the method involves adding sodium carbonate (Na₂CO₃) to control the pH of the reaction. Sodium carbonate can be added in parallel with sodium dithionite.
[0044] The method may further include a phase transfer catalyst (PTC). Preferred PTCs include tetraalkylammonium salts, such as tetrabutylammonium bisulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylammonium chloride, tetraethylammonium bromide, tetramethylammonium chloride, and tetramethylammonium bromide. Tetraethylammonium chloride is the most preferred PTC for this method.
[0045] The reaction is preferably carried out at a reaction temperature of 25°C to 50°C, and most preferably at a reaction temperature of 30°C to 40°C.
[0046] In the embodiment:
[0047] (1) The compound having formula II and 2-halogenated heptafluoropropane are combined in a reaction vessel.
[0048] (2) Heat the container to the reaction temperature, and
[0049] (3) Add sodium dithionite solution in a metered manner, at a rate that does not exceed the reaction temperature.
[0050] The method may further include recycling any unreacted compounds of formula II back into the reaction chamber. This recycling step allows for the use of excess formula II in the method.
[0051] Advantageously, the salts associated with the buffer solution can be removed after phase separation and washing with aqueous solution.
[0052] The methods described in this article can be used to prepare agrochemicals.
[0053] Compounds having formula I prepared by methods as defined herein are also provided.
[0054] Unless otherwise stated, all percentages are given as a percentage of total weight, and all embodiments and preferred features can be combined in any combination.
[0055] The present invention is described by way of the following non-limiting examples. Example
[0056] The following reaction scheme (reaction 1) is carried out as described below.
[0057]
[0058] Reaction 1
[0059] Example 1
[0060] Preparation of buffer solution
[0061] Citric acid (192 g, 1 mol) was dissolved in 500 g of water. The pH was adjusted to pH = 4.3 by adding 50% NaOH aqueous solution (142.5 g, 1.8 mol). The pH value was measured using a pH sensor.
[0062] Preparation of sodium dithionite solution
[0063] Under nitrogen atmosphere, an aqueous solution of sodium carbonate (21% by weight, 6.2 g, 12 mmol, 0.2 equivalents) was added to 30 g of water. Then, 7.1 g of sodium dithionite (85%, 35 mmol, 0.56 equivalents) was added to this solution to obtain a solution with pH = 9.1.
[0064] reaction
[0065] Equipment: 350 mL multi-necked reactor equipped with a top-mounted stirrer, pH sensor, internal thermometer, two feeding funnels (one containing sodium dithionite aqueous solution and the other containing 21% sodium carbonate aqueous solution), a gas scrubber containing 5% NaOH aqueous solution, and a nitrogen inlet.
[0066] Difluoromethoxyaniline (10.0 g, 63 mmol, 1.0 equivalent) was dissolved in EtOAc (45 mL). Tetraethylammonium chloride (0.1 g, 0.6 mmol, 0.01 equivalent), citric acid / sodium citrate buffer (20 g) (prepared as described above), and 10 g of water were added to the solution under stirring and a slow nitrogen flow.
[0067] The two-phase mixture was heated to T = 30°C, and then 2-iodoheptafluoropropane (25 g, 84 mmol, 1.3 equivalents) was added in a metered manner over 15 minutes.
[0068] Add sodium dithionite solution (prepared as described above) and 21% sodium carbonate aqueous solution to the reaction mixture in a parallel flow over 2 to 2.5 hours, maintaining the pH at pH = 4.2 - 4.6.
[0069] After adding all the sodium dithionite solution, the reaction mixture was stirred at T = 30°C for another hour, and an aqueous sodium carbonate solution was added to maintain pH = 4.2 - 4.6.
[0070] result
[0071] After GC analysis, the reactants were cooled to room temperature. The phases were separated (aqueous phase at the bottom), and the organic phase was washed with 2 x 25 g of water (aqueous phase at the top - reverse reaction). The solvent was removed under reduced pressure by a rotary evaporator to obtain the product, which was an orange liquid (18.3 g, 90% yield - mass loss was due to sampling during the reaction) with a strength of 95%.
[0072] 1 H, NMR (400 MHz, CDCl3) δ ppm: 7.30 (m, 2H), 6.85 (m, 1H), 6.51 (t, J= 73.6 Hz (HCF), 1H), 4.12 (br.s. 2H)
[0073] pass 1 H QNMR confirmed that the product was 2-difluoromethoxy-4-heptafluoroaniline, and the yield of the product was determined.
[0074] Example 2
[0075] Procedure using 2-iodoheptafluoropropane as a limiting reagent
[0076] Crude 2-difluoromethoxyaniline (82% by weight) (70 g, 0.36 mol, 1.0 equivalent) was added to a multi-necked reactor equipped with a top-mounted stirrer, internal pH probe, thermometer, reflux condenser and two independent feed ports (feed funnel or metering pump), followed by the addition of EtOAc (280 mL), tetraethylammonium chloride (0.4 g, 3.0 mmol, 1 mol%) and citrate buffer (140 g).
[0077] Heptafluoroisopropyl iodine (104 g, 0.35 mol, 0.95 equivalents) was added submerged in the reaction mixture. A slight exothermic event was observed during this addition (T = 22°C to T = 24°C). After all components were combined, the reactants were heated to T = 30°C.
[0078] When T = 30°C is reached, sodium dithionite is added in a metered manner over 2.5 to 3 hours. To maintain the desired pH at 4.1 < 4.6, a 21 wt% aqueous solution of Na₂CO₃ is added concurrently in a metered manner (gas evolution can be observed during metered addition of the base). The reaction progress is monitored by GC.
[0079] After completion, a vacuum (300 mbar) was applied for 1 hour to remove the byproduct heptafluoropropane. The reaction mixture was then cooled to room temperature to allow phase separation, and the organic phase was washed with 2 x 70 g water and 1 x 70 g 20 wt% sulfuric acid to remove unreacted aniline. The organic phase was then neutralized to pH 7-8 by adding 2 wt% NaOH. The phases were then separated, and the solvent was removed under reduced pressure to give the product, which was a brown to dark orange liquid (via...). 1 H₂QNMR confirmed a mass of 10⁶ g, with a yield of approximately 80%, and the solvent EtOAc was the main impurity.
[0080] The successful use of heptafluoroisopropyl iodine as a limiting reagent has environmental benefits, and excess of compounds of formula II can be recycled back into the method.
[0081] This invention is defined by the claims.
Claims
1. A method for preparing a compound having formula I: Equation I Where R 1 The group is selected from one or more of the following: alkyl, substituted alkyl, haloalkyl, cyanoalkyl, alkoxy, halogen, haloalkoxy, amino, aminoalkyl, alkylsulfonyl, arylsulfonyl, alkylthioalkyl, and hydroxyl, wherein n is selected from 1, 2, or 3. The method includes making a compound having formula II: Formula II With 2-haloheptafluoropropane, The reaction occurs in the presence of sodium dithionite (Na2S2O4) and an aqueous buffer solution. The aqueous buffer solution contains both acid and base.
2. The method according to claim 1, wherein R 1 Selected from one or more of the following: C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, chlorine, fluorine, iodine, C 1-3 Halogenated alkoxy, amino, amino C 1-3 Alkyl, arylsulfonyl, C 1-3 Alkyl thioalkyl and hydroxyl.
3. The method according to claim 1 or 2, wherein 2-haloheptafluoropropane is 2-iodoheptafluoropropane.
4. The method according to any one of the preceding claims, wherein the method is carried out at a pH of 3 to 5, preferably at a pH of 4 to 4.
5.
5. The method according to any one of the preceding claims, wherein the acid is a weak acid, preferably selected from citric acid, acetic acid, lactic acid, methylmaleic acid, tartaric acid, phosphoric acid and / or formic acid.
6. The method according to any one of the preceding claims, wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium acetate, and ammonium formate.
7. The method according to any one of the preceding claims, wherein the ratio of 2-haloheptafluoropropane to formula II is 0.8:1 to 2:
1.
8. The method according to any one of the preceding claims, wherein the method is carried out in the presence of an alcohol solvent, an ether solvent or an ester solvent, preferably in the presence of an ester solvent.
9. The method according to any one of the preceding claims, wherein the method further comprises adding sodium carbonate (Na2CO3).
10. The method according to any one of the preceding claims, wherein the method further comprises a phase transfer catalyst (PTC).
11. The method according to any one of the preceding claims, wherein the reaction is carried out at a reaction temperature of 25°C to 50°C, preferably at a reaction temperature of 30°C to 40°C.
12. The method of claim 11, wherein the compound having formula II and 2-halogenated heptafluoropropane are combined in a reaction vessel; Heat the container to the reaction temperature; and Sodium dithionite solution is added in a metered manner, at a rate that does not exceed the reaction temperature.
13. The method according to any one of the preceding claims, the method further comprising recycling any unreacted compound having formula II back into the reaction chamber.
14. A method for preparing agricultural chemicals, the method comprising any one of the preceding claims.
15. A compound having Formula I, said compound having Formula I being prepared by the method according to any one of claims 1 to 14.