PROCESS FOR THE PREPARATION OF 5-CHLORO-PYRIDINE-2-CARBOXYLIC ACIDS AND CARBOXYLATES WITH 3-SULFUR CONTAINING SUBSTITUENTS

Abstract

A process for the preparation of compound of formula I is provided: (I) where R.sub.1 and R.sub.2 are as defined in the description.

##STR00001##

Claims

1. A process for the preparation of a chloro-pyridine compound of formula (I): ##STR00025## wherein R.sub.1 is H or C.sub.1-C.sub.4alkyl; preferably R.sub.1 is methyl, ethyl or t-butyl, more preferably Ri is ethyl; and R.sub.2 is C.sub.1-C.sub.4alkyl; preferably R.sub.2 is ethyl; which process comprises: (A)reacting a compound of formula II ##STR00026## wherein Xa is fluoro or chloro; preferably Xa is chloro; with a thiol compound R.sub.3-S-R.sub.2 wherein R.sub.2 is as defined in formula I and R.sub.3 is H or an alkali metal ion; preferably R.sub.3 is H or sodium, in the presence of a suitable base, in an appropriate solvent (or diluent) having a dielectric constant less than 15; to produce a compound of formula (Ia) or a salt thereof ##STR00027## and, optionally, esterifying the compound of the formula (Ia) or a salt thereof in the presence of a compound of formula ROH, wherein R is C.sub.1-.sub.4alkyl; to produce the compound of formula (I) where R.sub.1 is C.sub.1-C.sub.4alkyl.

2. A process according to claim 1, wherein Xa is chloro; R.sub.1 is ethyl; R.sub.2 is ethyl; and R.sub.3 is sodium.

3. A process according to claim 1, wherein the suitable base is selected from an alkali metal carbonate or an alkali metal hydroxide, more preferably sodium or potassium carbonate, most preferably potassium carbonate.

4. A process according to claim 1, wherein the appropriate solvent (or diluent) is selected from those with a dielectric constant in the range from 1.5 to 15.

5. A process according to claim 4, wherein the appropriate solvent (or diluent) is selected from dioxane, methyltetrahydrofuran, toluene, anisole, pyridine; preferably dioxane, methyltetrahydrofurane or toluene.

6. A process according to claim 1, wherein the reaction of step a. is performed at temperatures between 0° C. and the boiling point of the reaction mixture, more preferably at temperatures between 20° C. and 100° C., most preferably in the temperature range of 60-100° C.

7. A compound of formula Ia, or an agrochemically acceptable salt of a compound of Ia: ##STR00028##

8. A compound of formula Ia-1: ##STR00029## where M is sodium, potassium or lithium; preferably sodium or lithium.

9. A compound of formula I-2, or an agrochemically acceptable salt of a compound of I-2: ##STR00030## wherein R.sub.1a is C.sub.1-4alkyl; preferably R.sub.1a is methyl, ethyl or t-butyl, more preferably R.sub.1a is ethyl.

10. A compound of formula I-2a, or an agrochemically acceptable salt of a compound of I-2a: ##STR00031## wherein R.sub.1b is C.sub.1-4alkyl; preferably R.sub.1b is methyl, ethyl or t-butyl, more preferably R.sub.1b is ethyl; and n is 1 or 2; preferably n is 2.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Having thus described the invention in general terms, reference will now be made to the accompanying drawing wherein: FIG. 1 is a diagram showing the observed selectivity in function of solvent dielectric constant. More specifically, FIG. 1 shows the correlation between the observed ortho- para-thiolation selectivity and the dielectric constant of the solvent in accordance with one embodiment of the invention.

[0040] This solvent-dependent phenomenon was further explored and a correlation between the observed selectivity and the dielectric constant of the solvent (Lide, D. R., ed. (2005) CRC Handbook of Chemistry and Physics (86.sup.th ed.). Boca Raton (FL): CRC Press. ISBN 0-8493-0486-5) was established as shown in FIG. 1.

PREPARATORY EXAMPLES

[0041] Throughout this description, LC/MS means Liquid Chromatography Mass Spectrometry and the following methods were used for the analysis of the compounds:

[0042] Method A: Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) 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

[0043] Temperature: 350° C., Cone Gas Flow: 50 I/h, Desolvation Gas Flow: 650 I/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, Temp: 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 (ml/min) 0.85.

[0044] 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 ions, 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 to 800 Da) and a H-Class UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Column:

[0045] Waters UPLC HSS T3 C18, 1.8 pm, 30 x 2.1 mm, Temp: 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 (mL/min) 0.6.

[0046] Example 1: Preparation of sodium;3,5-dichloropyridine-2-carboxylate (XIIIa)

##STR00017##

[0047] A mixture of 3,5-dichloropyridine-2-carboxylic acid (20.0 g, 104 mmol) and sodium hydroxide (1M 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 afford the desired product (94%, 22.0 g, 96.6 mmol, 93% yield) which was used without further purification.

[0048] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (d, J=2.20 Hz, 1 H) 8.38 (d, J=2.20 Hz, 1 H).

[0049] Example 2: Preparation of 5-chloro-3-ethvIsulfanyl-pyridine-2-carboxylic acid (VI)

##STR00018##

[0050] A round-bottomed flask was charged with sodium;3,5-dichloropyridine-2-carboxylate (94%, 4.00 g, 17.2 mmol). The flask was purged with argon and previously deoxygenated 2-methyltetrahydrofuran (86 mL) was added under argon. The reaction mixture was heated up 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). The insoluble particles were filtered off. The filtrate was heated up 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 few minutes. The obtained prepicitate was filtered hot and dried under reduced pressure to afford the desired product (94%, 2.30 g, 9.95 mmol, 58% yield).

[0051] LC-MS (method A): retention time 0.77 min, m/z 218 [M+H+].

[0052] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.34 Hz, 3 H) 3.02 (q, J=7.34 Hz, 2 H) 7.93 (d, J =1.83 Hz, 1 H) 8.41 (d, J =1.83 Hz, 1 H).

[0053] Example 3: Preparation of 5-chloro-3-ethvIsulfanyl-pyridine-2-carboxylic acid (VI)

##STR00019##

[0054] 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 previously deoxygenated 2-methyltetrahydrofuran (13 mL) was added at room temperature sodium ethanethiolate (0.920 g, 10.9 mmol, 2.10 equiv.). The reaction mixture was heated up 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 down to room temperature, the reaction mixture was diluted with water and 2-methyltetrahydrofuran was removed in vacuo. Acetonitrile (6 mL) was added, followed by dropwise addition of 1N hydrochloric acid (21 mL).

[0055] The resulting precipitate was filtered and dried under reduced pressure to afford the desired product (71%, 1.00 g, 3.27 mmol, 63% yield).

[0056] Example 4: Preparation of 3-chloro-5-ethylsulfanyl-pyridine-2-carboxylic acid (XVI)

##STR00020##

[0057] A solution of 3,5-dichloropyridine-2-carboxylic acid (0.500 g, 2.47 mmol) in dimethylsulfoxide (5.5 mL) was prepared and heated up to 100° C. Potassium carbonate (0.378 g, 2.60 mmol, 1.05 equiv.) was added and the reaction mixture was stirred at 100° C. for 1 hour. Sodium ethanethiolate (0.250 g, 2.97 mmol, 1.20 equiv.) was then added and the reaction mixture was kept stirring at 100° C. overnight. After cooling down 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.

[0058] Purification of the crude material by reverse-phase chromatography afforded the desired product as a white solid (0.536 mmol, 22% yield).

[0059] LC-MS (method A): retention time 0.74 min, m/z 218 [M+H+].

[0060] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (t, J=7.15 Hz, 3 H) 3.10 -3.18 (q, J=7.15 Hz, 2 H) 7.95 (d, J=2.20 Hz, 1 H) 8.44 (s, 1 H).

[0061] Example 5: Preparation of ethyl 5-chloro-3-ethylsulfanyl-pyridine-2-carboxylate

##STR00021##

[0062] To a suspension of 5-chloro-3-ethylsulfanyl-pyridine-2-carboxylic acid (2.35 g, 10.6 mmol) in ethanol (26 mL) was added slowly at room temperature sulfuric acid (0.575 mL, 10.6 mmol, 1.00 equiv.). The reaction mixture was heated up to 70° C. and stirred for 15 hours. After cooling down to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted in ethyl acetate, washed twice with sodium bicarbonate sat. aq., dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the desired product (90%, 2.55 g, 9.34 mmol, 88% yield) which was used without further purification.

[0063] LC-MS (method A): retention time 0.99 min, m/z 246 [M+H+].

[0064] .sup.1H NMR (400 MHz, chloroform-d) δ ppm 1.39-1.47 (m, 6 H) 2.93 (q, J=7.34 Hz, 2 H) 4.48 (q, J=7.21 Hz, 2 H) 7.62 (d, J=2.20 Hz, 1 H) 8.37 (d, J=1.83 Hz, 1 H).

[0065] Example 6: Preparation of ethyl 3-chloro-5-ethylsulfanyl-pyridine-2-carboxylate (VIIa)

##STR00022##

[0066] To a stirred solution of ethyl 3,5-dichloropyridine-2-carboxylate (96%, 0.200 g, 0.873 mmol) in toluene (2 mL) was added at 0° C. sodium ethanethiolate (0.122 g, 1.31 mmol, 1.50 equiv.). The reaction mixture was allowed to reach room temperature and was stirred first at this temperature for 24 hours, and then for 15 hours at 80° C. After cooling down to room temperature, a LC-MS sample was measured to determine the ratio of the formed products VIIa and Xa. The results gave 60% conversion of starting material and the formation of VIIa:Xa with a ratio of 1:1.9.

[0067] LC-MS (method B): retention time 1.08 min, m/z 246 [M+H+].

[0068] .sup.1H NMR (400 MHz, chloroform-d) δ ppm 1.36-1.47 (m, 6 H) 3.04 (q, J =7.42 Hz, 2 H) 4.47 (q, J =7.09 Hz, 2 H) 7.62 (d, J=2.08 Hz, 1 H) 8.42 (d, J =1.96 Hz, 1 H).

[0069] Example 7: Preparation of ethyl 3-chloro-5-ethylsulfanyl-pyridine-2-carboxylate (VIIa)

##STR00023##

[0070] To a stirred solution of ethyl 3,5-dichloropyridine-2-carboxylate (95%, 0.200 g, 0.863 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added at 0° C. sodium ethanethiolate (0.099 g, 1.04 mmol, 1.20 equiv.). The reaction mixture was allowed to reach room temperature and was stirred for 6 hours. A LC-MS sample was measured to determine the ratio of the formed products VIIa and Xa. The results gave 70% conversion of starting material and the formation of VIIa:Xa with a ratio of 1:10.2.

[0071] LC-MS (method B): retention time 1.08 min, m/z 246 [M+H+].

[0072] .sup.1H NMR (400 MHz, chloroform-d) δ ppm 1.36-1.47 (m, 6 H) 3.04 (q, J=7.42 Hz, 2 H) 4.47 (q, J =7.09 Hz, 2 H) 7.62 (d, J=2.08 Hz, 1 H) 8.42 (d, J=1.96 Hz, 1 H).

[0073] Example 8: Solvent effect on the thiolation reaction on sodium 3,5-dichloropyridine-2-carboxylate (XIIIa)

##STR00024##

[0074] A 5 mL microwave vial was charged with sodium;3,5-dichloropyridine-2-carboxylate (94%, 100 mg, 0.422 mmol). The vial was purged with argon and previously deoxygenated solvent (2.2 mL) was added under argon. The reaction mixture was heated up to 80° C. and sodium; ethanethiolate (42.6 mg, 0,507 mmol, 1.20 equiv.) was added. The reaction mixture was stirred for 3.5 hours at 80° C. After cooling down to room temperature, the reaction mixture was stopped and a NMR sample was measured to determine the ratio of the formed products (XIV) and (XV). The results are summarized in the table below.

TABLE-US-00001 Dielectric Conversion XV XIV Entry Solvent constant (%) (%) (%) 1 DMSO 46.7 99 88 12 2 DMA 37.8 87 64 36 3 DMF 36.7 82 67 33 4 Pyridine 12.4 87 11 89 5 Dimethoxyethane 7.2 82 10 90 6 2-MeTHF 6.97 93 9 91 7 Anisole 4.33 76 10 90 8 Dioxane 2.25 93 4 96