PROCESS FOR THE PREPARATION OF HERBICIDAL PYRIDINYLIMIDAZOLONE COMPOUNDS

Abstract

The present invention relates to a process for the preparation of a compound of formula wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined in the specification.

##STR00001##

Claims

1. A process for the preparation of compound of formula (I) ##STR00030## wherein R.sup.1 is selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy and aryl; R.sup.2 is selected from C.sub.1-C.sub.6 alkyl, aryl and hydrogen R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, nitro and halogen; comprising a) reacting the compound of formula (II) ##STR00031## wherein R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above with a strong base and a compound of formula (III) ##STR00032## wherein R.sup.1 and R.sup.2 are as defined above to a compound of formula (IV) ##STR00033## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above, and b) reacting the compound of formula (IV) with an oxidizing agent to produce a compound of formula (I) ##STR00034## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above.

2. The process of claim 1, wherein the base is an alkali metal alkoxide, an alkali metal amide, an organolithium reagent or sodium hydride.

3. The process of claim 1, wherein step (a) is carried out in the presence of a solvent.

4. The process of claim 3, wherein the solvent is a non-protic organic solvent.

5. The process of claim 1, wherein step (a) is carried out at a temperature from 20 C. to 100 C.

6. The process of claim 1, wherein the oxidizing agent is aqueous sodium hypochlorite, oxygen, Dess-Martin periodinane or dimethylsulfoxide in the presence of an activating agent.

7. The process of claim 1, wherein step (b) is carried out in the presence of a solvent.

8. The process of claim 7, wherein the solvents is a polar non-water miscible solvent.

9. The process of claim 1, wherein step (b) is carried out at a temperature from 10 C. to 100 C.

10. The process of claim 1, wherein the compound of formula (III) is prepared by reacting an amino alcohol of formula (V) ##STR00035## wherein R.sup.1 and R.sup.2 are as defined in claim 1 with a dialkyl carbonate in the presence of base.

11. The process of claim 10, wherein the dialkyl carbonate is dimethyl carbonate or diethyl carbonate.

12. The process of claim 10, wherein the base is a sodium or potassium alkoxide.

13. The process of claim 10, which is carried out in the presence of a solvent.

14. The process of claim 13, wherein the solvent is toluene, dimethyl carbonate, diethyl carbonate or dioxane.

15. The process of claim 10, which is carried out at a temperature from 10 C. to 150 C.

16. The process of claim 1, wherein R.sup.1 is selected from C.sub.1-C.sub.5 alkyl and C.sub.1-C.sub.5 alkoxy.

17. The process of claim 16, wherein R.sup.1 is selected from methyl and methoxy.

18. The process of claim 1, wherein R.sup.2 is selected from hydrogen and C.sub.1-C.sub.5 alkyl.

19. The process of claim 18, wherein R.sup.2 is selected from methyl and hydrogen.

20. The process of claim 1, wherein R.sup.3 is selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl and halo.

21. The process of claim 20, wherein R.sup.3 is selected from hydrogen, chloro, methyl, difluoromethyl and trifluoromethyl.

22. The process of claim 1, wherein R.sup.4 is selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl and halo.

23. The process of claim 22, wherein R.sup.4 is selected from hydrogen, chloro, methyl, difluoromethyl and trifluoromethyl.

24. The process of claim 1, wherein R.sup.5 is selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl and halo.

25. The process of claim 24, wherein R.sup.5 is selected from hydrogen, chloro, methyl, difluoromethyl and trifluoromethyl.

26. The process of claim 1, wherein R.sup.6 is selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl and halo.

27. The process of claim 26, wherein R.sup.6 is selected from hydrogen, chloro, methyl, difluoromethyl and trifluoromethyl.

28. A compound of formula (IVa) ##STR00036## wherein R.sup.1, R.sup.2 are as defined above; (i) one of R.sup.3, R.sup.4, R.sup.5 or R.sup.6 is C.sub.1-C.sub.6 haloalkyl and the other three are hydrogen; (ii) R.sup.4 or R.sup.5 is halo, the other is hydrogen and R.sup.3 and R.sup.6 are both hydrogen; or (iii) R.sup.5 is C.sub.1-C.sub.4 alkyl and R.sup.3, R.sup.4 and R.sup.6 are both hydrogen.

29. A compound of formula (IIIa): ##STR00037##

Description

EXAMPLES

[0051] The following abbreviations were used in this section: s=singlet; bs=broad singlet; d=doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, sept=septet; m=multiplet; RT=retention time, MH.sup.+=molecular mass of the molecular cation.

[0052] .sup.1H NMR spectra were recorded on a Bruker Avance III 400 spectrometer equipped with a BBFOplus probe at 400 MHz.

Example 1: Preparation of 1-(2-hydroxyethyl)-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea

[0053] ##STR00018##

[0054] To a mixture of 2-amino-4-(trifluoromethyl)-pyridine (5.00 g, 29.9 mmol) and sodium tert-butoxide (4.40 g, 44.9 mmol) was added dry toluene (22 ml). After stirring the resulting mixture for 5 min 3-methyl-1,3-oxazolidin-2-one (9.26 g, 89.8 mmol) was added. The resulting black solution was stirred for 3.5 h at ambient temperature. Towards the end the reaction mixture changed to a brown thick suspension. The reaction was quenched by addition of water and diluted with ethyl acetate. Phases were separated and the aqueous phase was extracted with EtOAc (2). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Evaporation under reduced pressure afforded 1-(2-hydroxyethyl)-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea (10.63 g) as a brown solid. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicated purity of 72% (97% chemical yield). Thus obtained material was recrystallized from EtOAc (50 ml) to provide 1-(2-hydroxyethyl)-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea (5.90 g, 75%, >99% purity) as a white crystalline solid.

[0055] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.99 (br, 1H), 8.30 (d, J=5.1 Hz, 1H), 8.25 (s, 1H), 7.11 (dd,J=5.3, 0.9 Hz, 1H), 4.39 (br, 1H), 3.90-3.84 (m, 2H), 3.55-3.50 (m, 2H), 3.03 (s, 3H); .sup.19F NMR (400 MHz, CDCl.sub.3) 64.96.

[0056] Alternatively, the same compound can be also obtained by carrying out the following procedure:

[0057] To a suspension of NaNH.sub.2 (0.092 g, 2.24 mmol) in dry THF (1.2 ml) was added a solution of 3-methyl-1,3-oxazolidin-2-one (0.309 g, 2.99 mmol) and 2-amino-4-(trifluoromethyl)-pyridine (0.250 g, 1.50 mmol) in a dry THF (1.0 ml) at 0 C. The resulting dark solution was stirred at 0 C for 30 min and at ambient temperature for 5 h. A beige suspension had formed at the end of the reaction. The reaction was quenched by addition of acetic acid (0.27 ml, 4.8 mmol), diluted with methylene chloride and the remaining precipitate was filtered off. The filtrate was evaporated under reduced pressure and dissolved in methylene chloride (10 ml). This solution was washed with aq saturated NaHCO.sub.3, aq saturated NH.sub.4Cl, water (2) and brine. The remaining organic phase was evaporated of afford 1-(2-hydroxyethyl)-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea (0.324 g) as a beige solid. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicated purity of 89% (73% chemical yield).

Example 2: Preparation of (2S)-2-(methoxyamino)propan-1-ol

[0058] ##STR00019##

[0059] To a suspension of lithium aluminum hydride (3.34 g, 87.9 mmol) in dry THF (200 ml) was added at 0 C. dropwise over 20 min a solution of (2S)-2-(methoxyamino)propanoate (15.0 g, 78% purity, 87.9 mmol) in dry THF (25 ml). The reaction mixture was stirred for 1 h and allowed to warm to ambient temperature (full conversion). The reaction mixture was cooled to 0 C. and water (4.28 ml) was slowly added followed by 15% aq NaOH (4.28 ml) and another portion of water (12.84 ml) while keeping the temperature below 5 C. The resulting mixture was stirred at ambient temperature for 30 min, diluted with THF (100 ml) and filtered through a pad of celite. The filtrate was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford crude material (10.40 g). A short path distillation (0.06 mbar, 36 C.) provided (2S)-2-(methoxyamino)propan-1-ol (6.32 g, 96% purity, 66% yield) as a colourless liquid.

[0060] Analytical data matches those reported in WO 2010/106071

Example 3: Preparation of (4S)-3-methoxy-4-methyl-oxazolidin-2-one

[0061] ##STR00020##

[0062] To a solution of (2S)-2-(methoxyamino)propan-1-ol (1.00 g, 88% purity, 8.37 mmol) in dry toluene (8.4 ml) was added diethyl carbonate (2.0 ml, 16.7 mmol) followed by KOtBu (0.094 g, 0.837 mmol). The resulting reaction mixture was heated at reflux for 19 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and quenched with 1M HCl. Phases were separated and organic phase was washed with water and brine. Organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to provide a crude material (0.94 g). Purification by silica gel chromatography (0-30% EtOAc in cyclohexane) afforded (4S)-3-methoxy-4-methyl-oxazolidin-2-one (0.720 g, 93% purity, 61% yield) as a colourless liquid.

[0063] .sup.1H NMR (400 MHz, CDCl.sub.3) 4.33 (dd, J=8.1, 7.0 Hz, 1H), 3.97-3.88 (m, 1H), 3.88-3.82 (m, 4H), 1.37 (d, J=6.2 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 158.8, 67.5, 64.0, 54.5, 15.8.

Example 4: Preparation of 1-[(1S)-2-hydroxy-1-methyl-ethyl]-1-methoxy-3-[4-(trifluoromethyl)-2-pyridyl]urea

[0064] ##STR00021##

[0065] 2-Amino-4-(trifluoromethyl)pyridine (6.576 g, 39.3 mmol) was dissolved in dry THF (26 ml) and the solution was cooled to 5 C. 2.0M NaOtBu in THF (19.7 ml, 39.3 mmol) was added over 10 min. After stirring at this temperature for 1 h a solution of (4S)-3-methoxy-4-methyl-oxazolidin-2-one (4.00 g, 26.23 mmol) in THF (4 ml) was added and stirring was continued for 1 h 15 min. The reaction mixture was quenched with 2M HCl to pH 3. The resulting mixture was extracted with DCM (3), combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Evaporation under reduced pressure provided 1-[(1S)-2-hydroxy-1-methyl-ethyl]-1-methoxy-3-[4-(trifluoromethyl)-2-pyridyl]urea (8.26 g, 86% purity, 92% chemical yield) as an orange oil which crystallized upon standing.

[0066] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.49 (d, J=5.1 Hz, 1H), 8.36-8.33 (m, 1H), 7.33 (dd, J=5.1, 1.1 Hz, 1H), 4.41-4.31 (m, 1H), 3.86 (s, 3H), 3.75 (dd, J=11.2, 8.6 Hz, 1H), 3.58 (dd, J=11.4, 5.5 Hz, 1H), 1.22 (d, J=7.0 Hz, 3H); .sup.19F NMR (400 MHz, CDCl.sub.3) 66.57.

Example 5: Preparation of 4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one

[0067] ##STR00022##

[0068] To a solution of 1-(2-hydroxyethyl)-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea (10.0 g, 36.1 mmol) in EtOAc (300 ml) was added NaBr (0.375 g, 3.60 mmol) and 4-acetylamino-TEMPO (0.393 g, 1.80 mmol). The resulting solution was cooled to 0 C. and 5% aqueous solution of NaOCl (54 ml, 39.7 mmol) adjusted to pH 9.5 by NaHCO.sub.3 (0.6 g) was added over 15 min. The color of the reaction mixture changed from pale yellow to orange. After stirring at 0 C. for 30 min another portion of 5% aq NaOCl (9.8 ml, 7.20 mmol) was added and the reaction was stirred for further 30 min. At this stage starting material was fully consumed. The reaction mixture was diluted with water, phases were separated and aqueous layer was extracted with EtOAc (3200 ml). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford crude material (10.0 g). This material was suspended in n-hexane (100 ml) and heated to 70 C. TBME (80 ml) was added and heating was continued for 30 min. The remaining solid was filtered off and the filtrate was slowly cooled to 0 C. The resulting precipitate was filtered, washed on filter with n-hexane and dried under high vacuum to afford 4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one (7.4 g, 75%) as a white solid.

[0069] Analytical data matches those reported in WO 2015/059262

Example 6: Preparation of (5S)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one

[0070] ##STR00023##

[0071] To a solution of 1-[(1S)-2-hydroxy-1-methyl-ethyl]-1-methoxy-3-[4-(trifluoromethyl)-2-pyridyl]urea (10.0 g, 96% purity, 32.7 mmol) in ethyl acetate (300 ml) was added NaBr (0.337 g, 3.27 mmol) and 4-acetamido-2,2,6,6-tetramethylpiperidino-1-oxyl (0.356 g, 1.64 mmol). The resulting suspension was cooled to 0 C. An aqueous solution of NaClO (5.0%, 57.8 ml, 36.0 mmol) adjusted to pH 9.5 by addition of NaHCO.sub.3 (1.05 g) was added over 10 min. After stirring for another 10 min (full conversion) the layers were separated, the organic layer was washed with water (2) and brine and dried over anhydrous Na.sub.2SO.sub.4. Evaporation under reduced pressure provided crude material (10.01 g) which was purified by trituration with n-pentane (220 ml) to afford (5S)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one (7.82 g, 95% purity, 78% yield) as an off white solid.

[0072] Analytical data matches those reported in WO 2015/052076

Example 7: Preparation of 3-(5-chloro-2-pyridyl)-1-(2-hydroxyethyl)-1-methyl-urea

[0073] ##STR00024##

[0074] Sodium hydride (60% in paraffin oil, 0.114 g, 2.86 mmol) was washed twice under Ar with n-hexane (2 ml). A solution of 2-amino-5-chloropyridine (0.250 g, 1.91 mmol) in 2-MeTHF (2.5 ml) was added slowly. The grey-green suspension was stirred until no more gas evolution was observed and then 3-methyl-2-oxazolidinone (0.393 g, 3.81 mmol) was added. The resulting reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by careful addition of water and diluted with EtOAc. Phases were separated and aqueous phase was extracted with EtOAc (2). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford a crude residue (0.428 g). Quantitative .sup.1H NMR analysis using trimethoxy benzene as an internal standard indicated purity of 71% (69% chemical yield). The crude product was purified by silica gel chromatography (eluting with 1-4% MeOH in DCM) to afford 3-(5-chloro-2-pyridyl)-1-(2-hydroxyethyl)-1-methyl-urea (0.233 g, 95% purity, 50%) as a white solid.

[0075] .sup.1H NMR (400 MHz, d.sub.6DMSO) 9.21 (br, 1H), 8.22 (dd, J=2.6, 0.7 Hz, 1H), 7.83-7.80 (m, 1H), 7.79-7.75 (m, 1H), 5.35 (br, 1H), 3.59 (q, J=5.1 Hz, 2H), 3.43-3.36 (m, 2H), 2.94 (s, 3H).

Example 8: Preparation of 1-(2-hydroxyethyl)-1-methyl-3-[5-(trifluoromethyl)-2-pyridyl]urea

[0076] ##STR00025##

[0077] Sodium hydride (60% in paraffin oil, 0.0907 g, 2.27 mmol) was washed twice under Ar with n-hexane (2 ml). A solution of 2-amino-5-chloropyridine (0.250 g, 1.51 mmol) in 2-MeTHF (2.0 ml) was added slowly. The brown-red suspension was stirred until no more gas evolution was observed and then 3-methyl-2-oxazolidinone (0.312 g, 3.02 mmol) was added. The resulting reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by careful addition of water and diluted with EtOAc. Phases were separated and aqueous phase was extracted with EtOAc (2). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford a crude residue (0.457 g). Quantitative .sup.1H NMR analysis using trimethoxy benzene as an internal standard indicated purity of 45% (52% chemical yield). The crude product was purified by silica gel chromatography (eluting with 1-4% MeOH in DCM) to afford 1-(2-hydroxyethyl)-1-methyl-3-[5-(trifluoromethyl)-2-pyridyl]urea (0.177 g, 99% purity, 44%) as a pale yellow solid.

[0078] .sup.1H NMR (400 MHz, d.sub.6DMSO) 9.56 (br, 1H), 8.56 (dd, J=1.5, 0.7 Hz, 1H), 8.03 (dd, J=9.0, 2.6 Hz, 1H), 7.97-7.93 (m, 1H), 5.42 (br, 1H), 3.62 (q, J=4.9 Hz, 2H), 3.46-3.38 (m, 2H), 2.96 (s, 3H).

Example 9: Preparation of 1-(2-hydroxyethyl)-1-methyl-3-(2-pyridyl)urea

[0079] ##STR00026##

[0080] To a solution of 2-amino pyridine (0.250 g, 2.63 mmol) in dry toluene (2.0 ml) was added 2.0M NaOtBu in THF (2.63 mmol, 5.26 mmol). After stirring for 5 min 3-methyl-2-oxazolidinone (1.36 g, 13.1 mmol) was added and the resulting solution was stirred at ambient temperature for 23 h. The reaction mixture was quenched by addition of water and diluted with EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2). The combined organic layers were washed with water and brine and dried over anhydrous Na.sub.2SO.sub.4. Evaporation under reduced pressure afforded crude 1-(2-hydroxyethyl)-1-methyl-3-(2-pyridyl)urea (0.849 g) as a yellow liquid. Quantitative .sup.1H NMR analysis using trimethoxy benzene as an internal standard indicated purity of 39% (65% chemical yield).

[0081] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.68 (br, 1H), 8.14-8.10 (m, 1H), 7.92-7.88 (m, 1H), 7.60 (ddd, J=8.7, 7.1, 2.2 Hz, 1H), 6.87 (ddd, J=7.3, 5.1, 1.1 Hz, 1H), 3.84-3.79 (m, 2H), 3.50-3.46 (m, 2H), 3.00 (s, 3H).

Example 10: Preparation of 1-(2-hydroxyethyl)-3-[6-(trifluoromethyl)-2-pyridyl]urea

[0082] ##STR00027##

[0083] Sodium hydride (60% in paraffin oil, 0.0886 g, 2.31 mmol) was washed twice under Ar with n-hexane (2 ml). A solution of 2-amino-5-chloropyridine (0.250 g, 1.54 mmol) in 2-MeTHF (2.0 ml) was added slowly. The gray suspension was stirred until no more gas evolution was observed and then 3-methyl-2-oxazolidinone (0.318 g, 3.08 mmol) was added. The resulting reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by careful addition of water and diluted with EtOAc. Phases were separated and aqueous phase was extracted with EtOAc (2). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford a crude residue (0.432 g). Quantitative .sup.1H NMR analysis using trimethoxy benzene as an internal standard indicated purity of 42% (48% chemical yield). The crude product was purified by silica gel chromatography (eluting with 1-4% MeOH in DCM) to afford 1-(2-hydroxyethyl)-3-[6-(trifluoromethyl)-2-pyridyl]urea (0.190 g, 97% purity, 45%) as a white solid.

[0084] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.18 (d, J=8.4 Hz, 1H), 8.14 (br, 1H), 7.78 (t, J=8.1 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 3.91-3.83 (m, 2H), 3.59-3.53 (m, 2H), 3.09 (s, 3H), 3.05 (br, 1H).

Example 11: Preparation of 3-(5-chloro-2-pyridyl)-1-(2-hydroxyethyl)-1-pentyl-urea

[0085] ##STR00028##

[0086] Sodium hydride (60% in paraffin oil, 0.110 g, 2.86 mmol) was washed with n-hexane (2 ml) under Ar. A solution of 2-amino-5-chloropyridine (0.25 g, 1.91 mmol) in 2-MeTHF (2.5 ml) was added slowly. The resulting grey-green suspension was stirred for 30 min at ambient temperature and then 3-pentyloxazolidin-2-one (0.655 g, 3.81 mmol) was added. The resulting brown suspension was stirred at room temperature for 4 h before being quenched by addition of water. EtOAc was added, phases were separated and aqueous phase was extracted with EtOAc (2). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Evaporation under reduced pressure afforded the crude product (0.793 g) as a brown liquid. Purification by silica gel chromatography (1-4% MeOH in DCM) afforded 3-(5-chloro-2-pyridyl)-1-(2-hydroxyethyl)-1-pentyl-urea (0.224 g, 89.5% purity, 37% yield) as a yellow solid.

[0087] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.08 (br, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.8, 2.6 Hz, 1H), 4.83 (br, 1H), 3.85 (t, J=4.6 Hz, 2H), 3.49 (t, J=4.6 Hz, 1H), 3.34-3.23 (m, 2H), 1.67-1.54 (m, 2H), 1.40-1.24 (m, 4H), 0.90 (t, J=7.0 Hz, 3H).

Example 12: Preparation of 1-(2-hydroxyethyl)-1-methyl-3-(4-methyl-2-pyridyl)urea

[0088] ##STR00029##

[0089] To a solution of 2-amino-4-methylpyridine (0.250 g, 2.29 mmol) in THF (3 ml) at 0 C was added a solution of sodium bis(trimethylsilyl)amine in THF (1.0M, 3.4 ml, 3.4 mmol). After stirring for 26 h at ambient temperature the reaction mixture was quenched by addition of water. The resulting mixture was taken up in EtOAc. Phases were separated and aqueous layer was extracted with EtOAc (2). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Evaporation under reduced pressure provided a crude residue (0.414 g) as a brown oil. Quantitative .sup.1H NMR analysis using trimethoxy benzene as an internal standard indicated purity of 48% (41% chemical yield). Analytically pure sample (pale yellow solid) was obtained by reverse phase HPLC (eluting with 5-20% MeCN in water).

[0090] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.88 (br, 1H), 8.01-7.95 (m, 2H), 6.81 (dd, J=5.3, 0.9 Hz, 1H), 3.90-3.85 (m, 2H), 3.62-3.56 (m, 2H), 3.07 (s, 3H), 2.38 (s, 3H).