Process for the preparation of 5-chloro-pyridine-2-carboxylic acid and formate esters having 3-sulfur-containing substituents

Abstract

A method for preparing a compound having formula I is provided: wherein R1 and R2 are as defined in the specification.

Description

[0001] The present invention relates to the preparation of 5-chloro-pyridine-2-carboxylic acid and formate esters having 3-sulfur-containing substituents which are useful intermediates for the preparation of agrochemicals.

[0002] More specifically, the present invention relates to 5-chloro-pyridine-2-carboxylic acid having formula I and to a process for its preparation

[0003]

[0004] wherein R1 is H or C1-C4 alkyl; R2 is C1-C4 alkyl; or an agrochemically acceptable salt of a compound of formula (I).

[0005] 5-Halo-pyridine-2-carboxylic acids and formates with 3-alkylsulfanyl substituents are useful intermediates for the preparation of biologically active compounds in the agrochemical industry, as previously described, for example, in WO 2016 / 005263, WO 2016 / 023954, WO 2016 / 030229, WO 2016 / 046071, WO 2016 / 059145, WO 2016 / 096584, WO 2016 / 104746, and WO 2019 / 065568.

[0006] The known synthesis of 5-halogen-pyridine-2-carboxylic acid and formate (Y) with 3-alkylsulfanyl substituent involves many reaction steps. For example, two routes to obtain 5-bromo compound (Y) have been reported (Route A: CN 105218437; Route B: US 2012 / 0165338 or J.Org.Chem. [Journal of Organic Chemistry] 2009, 74, 4547-4553), as shown in Scheme 1 (R1 is H, C1-C4 alkyl or alkali metal ion)

[0007]

[0008] Scheme 1. Pathway to obtain 5-Br compound (Y)

[0009] Obtaining the corresponding 5-iodo compound (Y) in seven steps from commercially available 5,6-dichloronicotinic acid has been reported in WO 2016 / 104746, as shown in Scheme 2.

[0010]

[0011] Scheme 2.5-Iodine compound (Y)

[0012] Obviously, such long and laborious syntheses are not suitable for the preparation of large quantities of materials due to the low overall yields and the large amounts of waste generated. It would therefore be advantageous to have more efficient and economical routes to these intermediates.

[0013] Furthermore, within the class of 5-halogen-3-alkylsulfanyl-pyridine-2-carboxylic acid esters, 5-chloro-3-alkylsulfanyl-pyridine-2-carboxylic acids and corresponding esters are not disclosed and their preparation routes are not clear. Due to the unavailability of chlorinated intermediates of formula (I), the synthetic community has been prompted to date to use bromine and iodine analogs to prepare bioactive agrochemicals (WO 2016 / 005263, WO 2016 / 096584, WO 2016 / 104746 WO 2016 / 023954, WO 2016 / 046071, WO 2016 / 087265, WO 2016 / 087257, WO 2016 / 030229, WO 2016 / 121997, WO 2016 / 104746). However, the use of building blocks of formula (I) in these syntheses will be very beneficial in reducing the formation of bromine- and iodine-containing wastes in subsequent 5-position functionalization reactions (metal-catalyzed cross-coupling reactions, nucleophilic aromatic substitutions, etc.), in favor of more benign chlorine-containing wastes. In addition, compounds of formula (I) can be considered as alternative convenient intermediates to significantly shorten the synthesis of other agrochemicals for which laborious and long routes were originally designed (WO 2019 / 065568, WO 2019 / 124529, WO2020 / 050212).

[0014] Commercially available 3,5-dichloropyridine-2-carboxylic acid (VIII) and its corresponding ester (IX) (wherein R1 is C1-C4 alkyl) can be convenient starting materials for intermediates of formula (VI) and (VII). In principle, all that is required is the selective displacement of the chlorine ortho to the formate group with ethylthiolate (Scheme 3).

[0015]

[0016] Scheme 3. Conceived pathways from (VIII) or (IX) to (VI) or (VII)

[0017] However, it is not obvious that such selectivity is achievable since the 2-carboxylate moiety renders the "ortho" position sterically less accessible and unfavorable for the formation of the desired 3-alkylsulfanyl product. Indeed, reacting compounds of formula (IXa) under standard conditions for nucleophilic aromatic substitution reactions preferentially afforded the undesired isomer (Xa) in all solvents tested (Scheme 4).

[0018]

[0019] Scheme 4. Observed selectivity of reaction of (IXa)

[0020] Ortho-selective thiolation of polychlorinated aromatic compounds with free acid moieties is challenging, rarely described, and is typically copper-mediated via carboxylate-directed Ullmann-type coupling (as described, for example, in Sambiagio C., Marsden SP, Blacker AJ, McGowan PC Chem. Soc. Rev., 2014, 43, 3525-3550), as shown in Scheme 5.

[0021]

[0022] Scheme 5. Cu-mediated Ullmann-type coupling on chlorobenzoic acid

[0023] For polychlorinated picolinic acids, no example of this reaction has ever been reported.

[0024] Therefore, according to the present invention, there is provided a process for preparing a compound having formula I (Scheme 6):

[0025]

[0026] wherein R1 is H or C1-C4 alkyl; preferably, R1 is methyl, ethyl or tert-butyl, more preferably, R1 is ethyl; and R2 is C1-C4 alkyl; preferably, R2 is ethyl; the method comprises:

[0027] (A) in the presence of a suitable base, in a suitable solvent (or diluent) having a dielectric constant of less than 15, a compound of formula II

[0028]

[0029] wherein Xa is fluorine or chlorine; preferably Xa is chlorine;

[0030] Reaction with a thiol compound R3-S-R2, wherein R2 is as defined in formula I and R3 is H or an alkali metal ion; preferably R3 is H, sodium, potassium or lithium;

[0031] To produce a compound having formula (Ia) or a salt thereof

[0032] and, optionally,

[0033] Esterifying the compound of formula (Ia) or a salt thereof in the presence of a compound of formula ROH, wherein R is C 1-4 to produce the compound having formula (I), wherein R1 is C1-C4 alkyl.

[0034] This approach proved to be of great usefulness as it allowed the synthesis of key building blocks for the preparation of agrochemicals in higher yields and under more favorable conditions relative to previously described routes.

[0035] The compounds of the formula I which are prepared by the process according to the invention and which have at least one basic center can form acid addition salts, for example, with strong inorganic acids (for example mineral acids, such as perchloric acid, sulfuric acid, nitric acid, nitrous acid, phosphoric acid or hydrohalic acids), strong organic carboxylic acids (for example unsubstituted or, for example, halogen-substituted C1-C4-alkanecarboxylic acids, such as acetic acid, for example saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid or phthalic acid, for example hydroxycarboxylic acids, such as ascorbic acid, lactic acid, malic acid, tartaric acid or citric acid, or for example benzoic acid), or organic sulfonic acids (for example unsubstituted or, for example, halogen-substituted C1-C4-alkanesulfonic acids or arylsulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid). Compounds of formula I having at least one acidic group can, for example, form salts with bases, such as mineral salts, for example alkali metal or alkaline earth metal salts, for example sodium, potassium, lithium or magnesium salts; or with ammonia or an organic amine (for example morpholine, piperidine, pyrrolidine, mono-, di- or tri-lower alkylamines, for example ethylamine, diethylamine, triethylamine or dimethylpropylamine, or mono-, di- or tri-hydroxy lower alkylamines, for example monoethanolamine, diethanolamine or triethanolamine).

[0036] In each case, the compound of formula (I) prepared by the process according to the invention is in free form or in the form of a salt (eg an agronomically usable salt).

[0037] The term "C1-C4 alkyl" as used herein refers to a saturated straight or branched hydrocarbon group having 1 to 4 carbon atoms attached via any of these carbon atoms, for example any of the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl.

[0038] Surprisingly, it was found that in the absence of any copper catalyst, high ortho selectivity was observed for the thiolation of 3,5-dichloropicolinic acid (compound of formula (II) represented by formula (VIII)) in aprotic non-polar solvents. In particular, the selectivity was found to be significantly affected by the nature of the solvent: in solvents with high relative dielectric constants (i.e., DMSO [dielectric constant of 46.7]), high selectivity was observed for the "para" isomer (XV), while in solvents with low relative dielectric constants (i.e., dioxane, toluene, 2-MeTHF ... [dielectric constants of 2.25, 2.38, 6.97]), selective formation of the "ortho" isomer (compound of formula (Ia) represented by formula (XIV)) was observed. This concept is shown in Scheme 6.

[0039]

[0040] Scheme 6. Observed selectivity of thiolation of (VIII)

[0041] In another embodiment of the present invention, there is provided a compound having formula I represented by a compound having formula Ia, or an agrochemically acceptable salt of a compound having formula Ia:

[0042]

[0043] In another embodiment of the present invention, a compound having formula I represented by a compound having formula Ia-1 is provided:

[0044]

[0045] wherein M is sodium, potassium or lithium; preferably sodium or lithium.

[0046] In yet another embodiment of the present invention, there is provided a compound having formula I represented by a compound having formula I-2, or an agrochemically acceptable salt of a compound having formula I-2:

[0047]

[0048] Where R 1a It is C 1-4 Alkyl; preferably R 1a is methyl, ethyl or tert-butyl, more preferably R 1a It is ethyl.

[0049] In another embodiment of the present invention, a compound having formula I-2a, or an agrochemically acceptable salt of a compound having formula I-2a is provided:

[0050]

[0051] Where R 1b It is C 1-4 Alkyl; preferably R 1b is methyl, ethyl or tert-butyl, more preferably R 1b is ethyl; and

[0052] n is 1 or 2; preferably n is 2.

[0053] Compounds of formula I-2a can be prepared by oxidizing compounds of formula I-2 by known methods, such as those described in WO 2016 / 005263.

[0054] In the method for producing a compound of formula (I) according to the present invention (Scheme 6), examples of suitable bases are alkali metal hydroxides or alkali metal carbonates. Examples that can be mentioned are sodium hydroxide, sodium carbonate, lithium hydroxide, potassium hydroxide and potassium carbonate; preferably alkali metal carbonates, more preferably sodium carbonate or potassium carbonate, most preferably potassium carbonate.

[0055] In the method for manufacturing a compound of formula (I) according to the present invention (Scheme 6), examples of suitable solvents (or diluents) are those having a dielectric constant of less than 15; more preferably, a solvent (or diluent) having a dielectric constant of less than 12; even more preferably, a solvent (or diluent) having a dielectric constant of less than 10. In another embodiment, the suitable solvent (or diluent) has a dielectric constant of less than 6. Examples of suitable solvents (or diluents) are dioxane, methyltetrahydrofuran, toluene, anisole, pyridine; more preferably, a non-polar organic (selected from dioxane, methyltetrahydrofuran or toluene); most preferably, suitable solvents are those having a dielectric constant in the range of from 1.5 to 15.

[0056] In one embodiment, in the process for producing a compound of formula (I) according to the present invention (Scheme 6), the reaction is advantageously carried out in a temperature range of from about 0°C to about +140°C, preferably from about 0°C to about +100°C, and in many cases in a range between ambient temperature and about +80°C. In a preferred embodiment, the reaction of step a. is carried out at a temperature between 0°C and the boiling point of the reaction mixture, more preferably at a temperature between 20°C and 100°C, and most preferably in a temperature range of 60°C-100°C.

[0057] In a preferred embodiment, the present invention provides a highly selective thiolation reaction of 3,5-dichloropicolinic acid compounds and the corresponding carboxylates of formula (II) using sodium ethanethiolate or ethanethiol and a base in a selected aprotic non-polar solvent having a dielectric constant of less than 15 under scalable conditions, wherein R1 is as defined in formula I, to produce 5-chloro-3-ethylsulfanyl-pyridine-2-carboxylic acid alkyl ester intermediates of formula (Ia) and (Ib).

[0058]

[0059] Where R4=C 1-4 alkyl BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Having described the invention in a general manner, reference will now be made to the accompanying drawings, in which: Figure 1 is a graph showing the observed selectivity for the solvent dielectric constant. More specifically, Figure 1The correlation between the observed ortho-para-thiolation selectivity and the dielectric constant of the solvent according to one embodiment of the present invention is shown.

[0061] This solvent dependence phenomenon was further explored and a correlation between the observed selectivity and the dielectric constant of the solvent was established (Lide, DR, ed. (2005) CRC Handbook of Chemistry and Physics (86th ed.) Boca Raton (FL): CRC Press ISBN 0-8493-0486-5), as Figure 1 shown.

[0062] Preparation Example:

[0063] Throughout this specification, LC / MS means liquid chromatography mass spectrometry, and the following method was used to analyze the compounds:

[0064] Method A : Spectra were recorded on a mass spectrometer from Waters (SQD, SQDII single quadrupole mass spectrometer), which was equipped with an electrospray source (polarity: positive and negative ions, capillary: 3.00 kV, cone range: 30 V, extractor: 2.00 V, source temperature: 150°C, desolvation temperature: 350°C, cone gas flow: 50 l / h, desolvation gas flow: 650 l / h; mass range: 100 to 900 Da) and an Acquity UPLC from Waters: binary pump, heated column compartment, diode array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, temperature: 60° C., DAD wavelength range (nm): 210 to 500, solvent gradient: A=water+5% MeOH+0.05% HCOOH, B=acetonitrile+0.05% HCOOH; gradient: 10%-100% B in 1.2 min; flow rate (ml / min) 0.85.

[0065] Method B: Spectra were recorded on a mass spectrometer from Waters (SQD single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive or negative, full scan, capillary: 3.00 kV, cone range: 41 V, source temperature: 150°C, desolvation temperature: 500°C, cone gas flow: 50 L / Hr, desolvation gas flow: 1000 L / Hr, mass range: 110 Da to 800 Da) and an H-Class UPLC from Waters: binary pump, heated column compartment and diode array detector. Column: Waters UPLC HSS T3 C18, 1.8 μm, 30×2.1 mm, temperature: 40°C, DAD wavelength range (nm): 200 to 400, solvent gradient: A = water + 5% acetonitrile + 0.1% HCOOH, B = acetonitrile + 0.05% HCOOH; Gradient: 0 min 10% B; 0.-0.2 min 10%-50% B; 0.2-0.7 min 50%-100% B; 0.7-1.3 min 100% B; 1.3-1.4 min 100%-10% B; 1.4-1.6 min 10% B; flow rate (mL / min) 0.6.

[0066] Example 1: Preparation of sodium 3,5-dichloropyridine-2-carboxylate (XIIIa)

[0067]

[0068] A mixture of 3,5-dichloropyridine-2-carboxylic acid (20.0 g, 104 mmol) and sodium hydroxide (1 M in water, 100 mL, 100 mmol, 0.96 equiv) was stirred at room temperature for 2 hours. The solution was filtered and the water was concentrated under reduced pressure to give the desired product (94%, 22.0 g, 96.6 mmol, 93% yield), which was used without further purification.

[0069] 1 H NMR (400MHz, DMSO-d6) δppm 8.04 (d, J = 2.20 Hz, 1H) 8.38 (d, J = 2.20 Hz, 1H).

[0070] Example 2: Preparation of 5-chloro-3-ethylsulfanyl-pyridine-2-carboxylic acid (VI)

[0071]

[0072] A round-bottom flask was charged with sodium 3,5-dichloropyridine-2-carboxylate (94%, 4.00 g, 17.2 mmol). The flask was purged with argon and pre-deoxygenated 2-methyltetrahydrofuran (86 mL) was added under argon. The reaction mixture was heated to 70 ° C, and sodium ethanethiolate (1.82 g, 20.6 mmol, 1.19 equiv.) was added. It was then stirred at 70 ° C for 7 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (29 mL) and acetonitrile (12 mL). Insoluble particles were filtered out. The filtrate was heated to 80 ° C, and additional water (10 mL) and acetonitrile (5 mL) were added. At 80 ° C, hot 1N hydrochloric acid (45 ° C, 16 mL) was added dropwise, and it was kept stirring for a few minutes. The obtained precipitate was hot filtered and dried under reduced pressure to obtain the desired product (94%, 2.30 g, 9.95 mmol, 58% yield).

[0073] LC-MS (method A): retention time 0.77 min, m / z 218 [M+H + ].

[0074] 1 H NMR (400MHz, DMSO-d6) δppm 1.25 (t, J = 7.34Hz, 3H) 3.02 (q, J = 7.34Hz, 2H) 7.93 (d, J = 1.83Hz, 1H) 8.41 (d, J = 1.83Hz, 1H).

[0075] Example 3: Preparation of 5-chloro-3-ethylsulfanyl-pyridine-2-carboxylic acid (VI)

[0076]

[0077] At room temperature, sodium ethanethiolate (0.920 g, 10.9 mmol, 2.10 equiv) was added to a stirred solution of 3,5-dichloropyridine-2-carboxylic acid (1.00 g, 5.21 mmol) and sodium carbonate (0.662 g, 6.25 mmol, 1.20 equiv) in pre-deoxygenated 2-methyltetrahydrofuran (13 mL). The reaction mixture was heated to 50 ° C and stirred for 3 hours. Additional 2-methyltetrahydrofuran (13 mL) was added, and the reaction mixture was stirred at 50 ° C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water, and 2-methyltetrahydrofuran was removed in vacuo. Acetonitrile (6 mL) was added, and 1N hydrochloric acid (21 mL) was then added dropwise. The resulting precipitate was filtered and dried under reduced pressure to obtain the desired product (71%, 1.00 g, 3.27 mmol, 63% yield).

[0078] Example 4: Preparation of 3-chloro-5-ethylsulfanyl-pyridine-2-carboxylic acid (XVI)

[0079]

[0080] A solution of 3,5-dichloropyridine-2-carboxylic acid (0.500g, 2.47mmol) in dimethyl sulfoxide (5.5mL) was prepared and heated to 100°C. Potassium carbonate (0.378g, 2.60mmol, 1.05 equivalents) was added, and the reaction mixture was stirred at 100°C for 1 hour. Sodium ethanethiolate (0.250g, 2.97mmol, 1.20 equivalents) was then added, and the reaction mixture was kept stirring overnight at 100°C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The aqueous layer was then acidified and extracted with more ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography to obtain the desired product (0.536mmol, 22% yield) as a white solid.

[0081] LC-MS (method A): retention time 0.74 min, m / z 218 [M+H + ].

[0082] 1 H NMR (400MHz, DMSO-d6) δppm 1.26 (t, J = 7.15Hz, 3H) 3.10-3.18 (q, J = 7.15Hz, 2H) 7.95 (d, J = 2.20Hz, 1H) 8.44 (s, 1H).

[0083] Example 5: Preparation of 5-chloro-3-ethylsulfanyl-pyridine-2-carboxylic acid ethyl ester

[0084]

[0085] To a suspension of 5-chloro-3-ethylsulfanyl-pyridine-2-carboxylic acid (2.35 g, 10.6 mmol) in ethanol (26 mL) was slowly added sulfuric acid (0.575 mL, 10.6 mmol, 1.00 equiv) at room temperature. The reaction mixture was heated to 70 °C and stirred for 15 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed twice with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired product (90%, 2.55 g, 9.34 mmol, 88% yield), which was used without further purification.

[0086] LC-MS (method A): retention time 0.99 min, m / z 246 [M+H + ].

[0087] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39-1.47 (m, 6H) 2.93 (q, J = 7.34 Hz, 2H) 4.48 (q, J = 7.21 Hz, 2H) 7.62 (d, J = 2.20 Hz, 1H) 8.37 (d, J = 1.83 Hz, 1H).

[0088] Example 6: Preparation of 3-chloro-5-ethylsulfanyl-pyridine-2-carboxylic acid ethyl ester (VIIa)

[0089]

[0090] At 0 ° C, sodium ethanethiolate (0.122 g, 1.31 mmol, 1.50 equivalents) was added to a stirred solution of ethyl 3,5-dichloropyridine-2-carboxylate (96%, 0.200 g, 0.873 mmol) in toluene (2 mL). The reaction mixture was allowed to reach room temperature and first stirred at this temperature for 24 hours, and then stirred at 80 ° C for 15 hours. After cooling to room temperature, LC-MS samples were measured to determine the ratio of the formed products VIIa and Xa. The results gave a 60% conversion of the starting material and a 1: 1.9 ratio of VIIa: Xa.

[0091] LC-MS (method B): retention time 1.08 min, m / z 246 [M+H + ].

[0092] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.47 (m, 6H) 3.04 (q, J = 7.42 Hz, 2H) 4.47 (q, J = 7.09 Hz, 2H) 7.62 (d, J = 2.08 Hz, 1H) 8.42 (d, J = 1.96 Hz, 1H).

[0093] Example 7: Preparation of 3-chloro-5-ethylsulfanyl-pyridine-2-carboxylic acid ethyl ester (VIIa)

[0094]

[0095] At 0 ° C, sodium ethanethiolate (0.099 g, 1.04 mmol, 1.20 equiv.) was added to a stirred solution of ethyl 3,5-dichloropyridine-2-carboxylate (95%, 0.200 g, 0.863 mmol) in 1-methyl-2-pyrrolidone (2 mL). The reaction mixture was allowed to reach room temperature and stirred for 6 hours. LC-MS samples were measured to determine the ratio of the products VIIa and Xa formed. The results gave a 70% conversion of the starting material and a 1:10.2 ratio of VIIa:Xa.

[0096] LC-MS (method B): retention time 1.08 min, m / z 246 [M+H+ ].

[0097] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.47 (m, 6H) 3.04 (q, J = 7.42 Hz, 2H) 4.47 (q, J = 7.09 Hz, 2H) 7.62 (d, J = 2.08 Hz, 1H) 8.42 (d, J = 1.96 Hz, 1H).

[0098] Example 8: Effect of solvent on the thiolation reaction of sodium 3,5-dichloropyridine-2-carboxylate (XIIIa)

[0099]

[0100] 3,5-Dichloropyridine-2-sodium formate (94%, 100 mg, 0.422 mmol) was loaded into a 5 mL microwave vial. The vial was purged with argon and a pre-deoxygenated solvent (2.2 mL) was added under argon. The reaction mixture was heated to 80 ° C and sodium ethanethiolate (42.6 mg, 0.507 mmol, 1.20 equivalents) was added. The reaction mixture was stirred at 80 ° C for 3.5 hours. After cooling to room temperature, the reaction mixture was stopped and an NMR sample was measured to determine the ratio of the formed products (XIV) and (XV). The results are summarized in the table below.

[0101]

Claims

1. A method for preparing a chloro-pyridine compound having formula (I): wherein R1 is H or C1-C4 alkyl; and R2 is C1-C4 alkyl; the method comprises: (A) in the temperature range of from 0°C to +140°C, in the presence of a suitable base, in a suitable solvent or diluent, reacting a compound of formula II (II) wherein Xa is fluorine or chlorine; reacting with a thiol compound R3-S-R2, wherein R2 is as defined in formula I and R3 is H or an alkali metal ion; To produce a compound having formula (Ia) or a salt thereof (It); The suitable solvent or diluent is selected from dioxane, methyltetrahydrofuran, toluene, anisole and pyridine; and, optionally, Esterifying the compound of formula (Ia) or a salt thereof in the presence of a compound of formula ROH, wherein R is C 1-4 to produce the compound having formula (I), wherein R1 is C1-C4 alkyl.

2. The method according to claim 1, wherein: Xa is chlorine; R1 is ethyl; R2 is ethyl; and R3 is sodium.

3. The method according to claim 1, wherein: The suitable base is selected from alkali metal carbonates or alkali metal hydroxides.

4. The method according to claim 1, wherein: The suitable solvent or diluent is selected from dimethoxyethane, methyltetrahydrofuran, anisole and dioxane.

5. The method according to claim 1, wherein: The suitable solvent or diluent is selected from dioxane, methyltetrahydrofuran and toluene.

6. The method according to claim 1, wherein: The reaction of step (A) is carried out at a temperature between 20°C and 100°C.

7. A compound of formula Ia, or an agrochemically acceptable salt of a compound of formula Ia: (It)。 8. A compound having formula Ia-1: (I-1) wherein M is sodium, potassium or lithium.

9. A compound of formula I-2, or an agrochemically acceptable salt of a compound of formula I-2: (I-2) Where R 1a It is C 1-4 alkyl.

10. A compound of formula I-2a, or an agrochemically acceptable salt of a compound of formula I-2a: (1-2a) Where R 1b It is C 1-4 Alkyl; and n is 1 or 2.

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