PROCESS FOR THE PREPARATION OF 5-CHLORO-3-ALKYLSULFANYL-PYRIDINE-2-CARBOXYLIC ACID AMIDES AND CARBOXYLATES

Abstract

##STR00001##

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

Claims

1. A process for the preparation of a 5-chloro pyridine-2-carboxylic acid amide of formula I: ##STR00024## wherein R.sub.1 is hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4hydroxyalkyl, C.sub.3-C.sub.7cycloalkyl, aryl or optionally substituted heteroaryl; and R.sub.2 is C.sub.1-C.sub.4alkyl; or an agrochemically acceptable salt of a compound of formula (I); which process comprises: reacting a compound of formula (III) ##STR00025## with a thiol compound R.sub.4—S—R.sub.2 wherein R.sub.2 is as defined in formula I and R.sub.4 is H or an alkali metal ion; 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 (I) or a salt thereof and, optionally, hydrolyzing the compound of the formula (I) or a salt thereof under either basic or acidic conditions; to produce the compound of formula (II) ##STR00026## where R.sub.2 is as defined in formula I and R.sub.3 is hydrogen, sodium, potassium or lithium.

2. A process according to claim 1, wherein R.sub.1 is hydrogen, C.sub.1-C.sub.2alkyl, Ci-C.sub.2hydroxyalkyl, C.sub.3-C.sub.5cycloalkyl, phenyl, pyridyl, or pyridyl which can be mono- or disubstituted by amino, methylamino or trifluoromethyl and R.sub.2 is C.sub.1-C.sub.2alkyl; preferably R.sub.1 is methyl or hydrogen and R.sub.2 is ethyl.

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 or sodium hydroxide, most preferably sodium hydroxide.

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, THF, methyltetrahydrofuran, toluene, anisole, pyridine, acetone, methylisobutyl ketone, tBuOH; preferably dioxane, methyltetrahydrofuran or methylisobutyl ketone.

6. A process according to claim 1, wherein the process is carried out in a temperature range of 0° C. to 100° C., preferably from 0° C. to 50° C.

7. A process according to claim 6, wherein the process is carried out at ambient temperature.

8. A compound of formula IV: ##STR00027## wherein R.sub.1 is hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4hydroxyalkyl, C.sub.3-C.sub.7cycloalkyl, aryl or optionally substituted heteroaryl; or an agrochemically acceptable salt of a compound of IV.

9. A compound according to claim 8, wherein R.sub.1 is hydrogen, C.sub.1-C.sub.2alkyl, C.sub.1-C.sub.2hydroxyalkyl, C.sub.3-C.sub.5cycloalkyl, phenyl, pyridyl, or pyridyl which can be mono- or disubstituted by amino, methylamino or trifluoromethyl.

10. A compound according to claim 8, wherein R.sub.1 is hydrogen, methyl, ethyl, phenyl, cyclopropyl, cyclopentyl, hydroxymethyl, hydroxyethyl, pyridyl or 2-(methylamino)-5-(trifluoromethyl)-3-pyridyl;_preferably R.sub.1 is hydrogen, ethyl, phenyl, cyclopentyl, hydroxyethyl or 2-(methylamino)-5-(trifluoromethyl)-3-pyridyl.

Description

PREPARATORY EXAMPLES

[0036] Purity of starting materials and products was determined with quantitative .sup.1H NMR using 1,3,5-trimethoxy benzene as an internal standard.

[0037] Example 1: Preparation of 5-chloro-3-ethylsulfanyl-pyridine-2-carboxamide

##STR00016##

[0038] 3,5-dichloropyridine-2-carboxamide (6.50 g, 95% purity, 32.5 mmol) and EtSNa (3.33 g, 82% purity, 32.5 mmol) were suspended in MeTHF (100 ml) and the light brown suspension was stirred at ambient temperature. Extra amount of EtSNa (2 × 0.167 g,82% purity, 1.62 mmol) was added after 2 and 4 h of reaction time. After a total reaction time of 5 h the reaction solution was extracted with water (50 ml), aqueous phase was extracted with EtOAc (2×50 ml) and the combined organic layers were washed with brine, dried over anhydrous MgSO.sub.4 and evaporated under reduced pressure. Drying under high vacuum provided 5-chloro-3-ethylsulfanyl-pyridine-2-carboxamide (7.36 g, 94% purity, 97% yield) as a white powder.

[0039] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (d, J = 2.2 Hz, 1 H), 8.01 (br s, 1 H), 7.85 (d, J = 2.2 Hz, 1 H), 7.61 (br s, 1 H), 2.93 (q, J = 7.3 Hz, 2 H), 1.25 (t, J = 7.3 Hz, 3 H)

Example 1a: Alternative Procedure for Preparation of 5-Chloro-3-Ethylsulfanyl-Pyridine-2-Carboxamide

[0040] A 1 L double jacketed glass reactor with an overhead stirrer was charged with 3,5-dichloropyridine-2-carboxamide (100.0 g, 0.52 mol) and Me—THF (400 g). The solids dissolved upon stirring to afford a homogenous colorless solution. Solid NaOH (31.5 g, 0.79 mol) was added in a single portion. To this suspension ethanethiol (32.5 g, 0.52 mol) was added dropwise over 40 min, as addition is exothermic cooling was applied to maintain Ti = 25° C. After full addition, mixture was stirred at Ti = 25° C. for 90 min and then heated to Ti = 65° C. for 120 min. After this period full completion was attained, water (100 g) was added and the biphasic mixture stirred for 10 min at Ti = 65° C. Phases were separated and organic layer was washed with water (2 × 60 g) at Ti = 65° C. Organic phase was partially concentrated by distilling off 250 g of solvent. Antisolvent methylcyclohexane (150 g) was added at Ti = 65° C. and the homogenous mixture was cooled to Ti = 25° C. over 60 min. During the cooling product started to crystallize from the solution.

[0041] Solids were filtered, washed with 2 × 50 g of methylcyclohexane and dried under reduced pressure to afford 5-chloro-3-ethylsulfanyl-pyridine-2-carboxamide (96 g, 80% yield) as a white solid.

[0042] Example 2: Solvent screening for preparation of 5-chloro-3-ethylsulfanyl-pyridine-2-carboxamide

##STR00017##

[0043] 3,5-dichloropyridine-2-carboxamide (50-100 mg) and NaSEt (1.1 eq) were suspended/dissolved in a given solvent and stirred for 5 h at ambient temperature. The reaction mixture was then diluted with EtOAc, washed with water and brine, organic layer dried over anhydrous MgSO.sub.4 and evaporated under reduced pressure. The resulting crude mixture was analyzed by .sup.1H NMR giving the product ratios shown in the table below.

TABLE-US-00001 Solvent A B C D MeTHF 1 98 0 1 NMP 26 29 12 33 DMF 39 33 14 14 Pyridine 16 75 7 2 Anisole 22 75 3 0 Dioxane 22.5 75 2.5 0

[0044] Example 3: Preparation of 5-chloro-3-ethylsulfanyl-pyridine-2-carboxylic acid

##STR00018##

[0045] 5-chloro-3-ethylsulfanyl-pyridine-2-carboxamide (0.500 g, 95% purity, 2.19 mmol) was suspended in aqueous 3 M NaOH (3.3 ml, 6.6 mmol) and the resulting mixture was heated at 100° C. for 20 h. The reaction mixture was cooled to ambient temperature and acidified to ca pH 3 with 2 M HCl. The resulting precipitate was filtered off, washed on filter with cold water and dried under high vacuum to yield 5-chloro-3-ethylsulfanyl-pyridine-2-carboxylic acid (0.505 g, 91% purity, 96% yield) as a slightly pink powder.

[0046] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H), 7.95 (d, J = 2.2 Hz, 1 H), 3.14 (q, J = 7.1 Hz, 2 H), 1.26 (t, J= 7.1 Hz, 3 H)

[0047] Example 4: Preparation of 5-chloro-N-ethyl-3-ethylsulfanyl-pyridine-2-carboxamide

##STR00019##

[0048] To a solution of 3,5-dichloro-N-ethyl-pyridine-2-carboxamide (0.100 g, 0.456 mmol) in THF (1.4 ml) was added NaSEt (0.052 g, 82% purity, 0.502 mmol) and the resulting suspension was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous MgSO.sub.4 and evaporated under reduced pressure to yield 5-chloro-N-ethyl-3-ethylsulfanyl-pyridine-2-carboxamide (0.103 g, 80% purity, 75% yield) as an off-white powder. About 3% of undesired isomer was also detected in addition to ca 15% unreacted starting material.

[0049] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.17 (d, J = 1.8 Hz, 1 H), 7.87 (br s, 1 H), 7.59 (d, J = 1.8 Hz, 1 H), 3.52-3.43 (m, 2 H), 2.88 (q, J = 7.5 Hz, 2 H), 1.42 (t, J = 7.3 Hz, 3 H), 1.25 (t, J = 7.3 Hz, 3 H)

[0050] Example 5: Preparation of 5-chloro-3-ethylsulfanyl-N-phenyl-pyridine-2-carboxamide

##STR00020##

[0051] To a solution of 3,5-dichloro-N-phenyl-pyridine-2-carboxamide (0.100 g, 0.374 mmol) in THF (1.2 ml) was added NaSEt (0.042 g, 82% purity, 0.412 mmol) and the resulting suspension was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous MgSO.sub.4 and evaporated under reduced pressure to yield 5-chloro-3-ethylsulfanyl-N-phenyl-pyridine-2-carboxamide (0.096 g, 83% purity, 73% yield) as an orange solid. About 10% of unreacted starting material, but none of the undesired isomers, were also detected.

[0052] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.92 (br s, 1 H), 8.26 (d, J = 1.8 Hz, 1 H), 7.80-7.75 (m, 2 H), 7.66 (d, J = 1.8 Hz, 1 H), 7.41-7.35 (m, 2 H), 7.17-7.12 (m, 1 H), 2.94 (q, J = 7.3 Hz, 2 H), 1.46 (t, J = 7.3 Hz, 3 H)

[0053] Example 6: Preparation of 5-chloro-N-cyclopentyl-3-ethylsulfanyl-pyridine-2-carboxamide

##STR00021##

[0054] To a solution of 3,5-dichloro-N-cyclopentyl-pyridine-2-carboxamide (0.100 g, 0.386 mmol) in THF (1.2 ml) was added NaSEt (0.044 g, 82% purity, 0.43 mmol) and the resulting suspension was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous MgSO.sub.4 and evaporated under reduced pressure to yield 5-chloro-N-cyclopentyl-3-ethylsulfanyl-pyridine-2-carboxamide (0.091 g, 87% purity, 72% yield) as an orange solid. About 10% of unreacted starting material, but none of the undesired isomers, were also detected.

[0055] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.16 (d, J = 2.2 Hz, 1 H), 7.85 (br s, 1 H), 7.58 (d, J = 2.2 Hz, 1 H), 4.41-4.30 (m, 1 H), 2.88 (q, J = 7.3 Hz, 2 H), 2.13-2.02 (m, 2 H), 1.79-1.49 (m, 6 H), 1.42 (t, J = 7.3 Hz, 3 H)

[0056] Example 7: Preparation of 5-chloro-3-ethylsulfanyl-N-(2-hydroxyethyl)pyridine-2-carboxamide

##STR00022##

[0057] To a solution of 3,5-dichloro-N-(2-hydroxyethyl)pyridine-2-carboxamide (0.100 g, 93% purity, 0.396 mmol) in THF (1.2 ml) was added NaSEt (0.045 g, 82% purity, 0.44 mmol) and the resulting suspension was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous MgSO.sub.4 and evaporated under reduced pressure to yield 5-chloro-3-ethylsulfanyl-N-(2-hydroxyethyl)pyridine-2-carboxamide (0.084 g, 82% purity, 67% yield) as an orange solid. About 1% of undesired isomer was also detected in addition to 11% unreacted starting material.

[0058] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.28 (br s, 1 H), 8.19 (d, J = 1.8 Hz, 1 H), 7.60 (d, J = 1.8 Hz, 1 H), 3.87-3.81 (m, 2 H), 3.66-3.59 (m, 2 H), 2.90 (q, J = 7.3 Hz, 2 H), 2.38 (br s, 1 H), 1.43 (t, J = 7.3 Hz, 3 H)

[0059] Example 8: Preparation of 5-chloro-3-ethylsulfanyl-N-[2-(methylamino)-5-(trifluoromethyl)-3-pyridyl] pyridine-2-carboxamide

##STR00023##

[0060] 3,5-dichloro-N-[2-(methylamino)-5-(trifluoromethyl)-3-pyridyl]pyridine-2-carboxamide (1.500 g, 94% purity, 3.85 mmol) was dissolved in THF (15.4 ml) and EtSNa (0.647 g, 80% purity, 6.15 mmol) was added to the mixture. The reaction was stirred 1 h15 min at 65° C. (brownish solution), then at room temperature overnight. It was then quenched with water (10 ml), diluted with EtOAc (20 ml), the phases were separated, and the aqueous phase was extracted twice with EtOAc (2×20 ml). The combined organic layers were then washed with brine (2×20 ml), dried over solid Na.sub.2SO.sub.4, filtered and the solvents were evaporated yielding a crude product (1.5595 g, purity 90%, chemical yield 94%). The crude was then purified by column chromatography, yielding 5-chloro-3-ethylsulfanyl-N-[2-(methylamino)-5-(trifluoromethyl)-3-pyridyl]pyridine-2-carboxamide (1.396 g purity 93%, isolated yield 91%) as a yellow solid.

[0061] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.47 (s, 1 H), 8.35 (d, J= 2.2 Hz, 1 H), 8.27 (d, J= 2.2 Hz, 1 H), 7.93 (d, J = 2.2 Hz, 1 H), 7.68 (d, J = 2.2 Hz, 1 H), 5.05 (bd, J = 4.4 Hz, 1 H), 5.05 (bd, J = 4.4 Hz, 1 H), 3.09 (d, J= 5.1 Hz, 3 H), 2.95 (q, J= 7.4 Hz, 2 H), 1.46 (t, J= 7.4 Hz, 3 H),