methyl 2-chloro-4-methoxy-3-oxobutanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of CH3O2CCH(Cl)COCH2OCH3 (68 mmole, 1.2 eq), prepared according to De Kimpe et al., Synthesis, 188 (1986), in absolute EtOH (75 ml) was treated with thiobenzamide (7.8 g, 56.7 mmole, 1.0 eq) and the resulting brown mixture refluxed under nitrogen for 8 hours. The mixture was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was washed with water twice and brine, then dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. Silica gel chromatography eluting with (9:1) hexanes-ethyl acetate provided 6.98 g (47%) of title compound as a yellow crystalline solid. 1H NMR (CDCl3): δ 3.6 (s, 3H), 3.9 (s, 3H), 4.95 (s, 2H), 7.4-7.5 (m, 3H), 8.0 (m, 2H). the resulting brown mixture refluxed under nitrogen for 8 hours The mixture was partitioned between ethyl acetate and saturated NaHCO3 The organic layer was washed with water twice brine, then dried over anhydrous sodium sulfate concentrated in vacuo to give a brown oil Silica gel chromatography eluting with (9:1) hexanes-ethyl acetate

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100 mL round-bottomed flask was added methyl 4-methoxy-3-oxobutanoate (4.43 mL, 34.2 mmol) and DCM (30.00 mL). Sulfuryl chloride (2.91 mL, 35.9 mmol) was added dropwise with a syringe to the reaction mixture. The mixture was then stirred for 1 hour at 20° C. The solution was reduced to an oil under reduced pressure and dissolved in EtOH (50 mL). To this solution was added methyl 2-chloro-4-methoxy-3-oxobutanoate (6.18 g, 34 mmol) and thiourea (1.9 mL, 34 mmol). The reaction was then stirred at reflux for approximately 12 hours. LCMS indicated that the reaction was complete, and the solvent was removed under reduced pressure. Saturated aqueous sodium bicarbonate was added, and the resulting solid was filtered and recrystallized from water and <5 mL EtOH to give methyl 2-amino-4-(methoxymethyl)thiazole-5-carboxylate as rust colored crystals (4.85 g, 68%). LCMS (M+H) 203 calc. for C7H11N2O3S 203.2. 1H NMR (400 MHz, CD3OD): δ ppm 4.64 (s, 2H), 3.77 (s, 3H), 3.37 (s, 3H). The reaction was then stirred at reflux for approximately 12 hours the solvent was removed under reduced pressure Saturated aqueous sodium bicarbonate was added the resulting solid was filtered recrystallized from water and <5 mL EtOH

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100 mL round-bottomed flask was added methyl 4-methoxy-3-oxobutanoate (4.43 mL, 34.2 mmol) and DCM (30.00 mL). Sulfuryl chloride (2.91 mL, 35.9 mmol) was added dropwise with a syringe to the reaction mixture. The mixture was then stirred for 1 hour at 20° C. The solution was reduced to an oil under reduced pressure and dissolved in EtOH (50 mL). To this solution was added methyl 2-chloro-4-methoxy-3-oxobutanoate (6.18 g, 34 mmol) and thiourea (1.9 mL, 34 mmol). The reaction was then stirred at reflux for approximately 12 hours. LCMS indicated that the reaction was complete, and the solvent was removed under reduced pressure. Saturated aqueous sodium bicarbonate was added, and the resulting solid was filtered and recrystallized from water and <5 mL EtOH to give methyl 2-amino-4-(methoxymethyl)thiazole-5-carboxylate as rust colored crystals (4.85 g, 68%). LCMS (M+H) 203 calc. for C7H11N2O3S 203.2. 1H NMR (400 MHz, CD3OD): δ ppm 4.64 (s, 2H), 3.77 (s, 3H), 3.37 (s, 3H). The reaction was then stirred at reflux for approximately 12 hours the solvent was removed under reduced pressure Saturated aqueous sodium bicarbonate was added the resulting solid was filtered recrystallized from water and <5 mL EtOH

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of CH3O2CCH(Cl)COCH2OCH3 (68 mmole, 1.2 eq), prepared according to De Kimpe et al., Synthesis, 188 (1986), in absolute EtOH (75 ml) was treated with thiobenzamide (7.8 g, 56.7 mmole, 1.0 eq) and the resulting brown mixture refluxed under nitrogen for 8 hours. The mixture was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was washed with water twice and brine, then dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. Silica gel chromatography eluting with (9:1) hexanes-ethyl acetate provided 6.98 g (47%) of title compound as a yellow crystalline solid. 1H NMR (CDCl3): δ 3.6 (s, 3H), 3.9 (s, 3H), 4.95 (s, 2H), 7.4-7.5 (m, 3H), 8.0 (m, 2H). the resulting brown mixture refluxed under nitrogen for 8 hours The mixture was partitioned between ethyl acetate and saturated NaHCO3 The organic layer was washed with water twice brine, then dried over anhydrous sodium sulfate concentrated in vacuo to give a brown oil Silica gel chromatography eluting with (9:1) hexanes-ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of CH3O2CCH(Cl)COCH2OCH3 (68 mmole, 1.2 eq), prepared according to De Kimpe et al., Synthesis, 188 (1986), in absolute EtOH (75 ml) was treated with thiobenzamide (7.8 g, 56.7 mmole, 1.0 eq) and the resulting brown mixture refluxed under nitrogen for 8 hours. The mixture was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was washed with water twice and brine, then dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. Silica gel chromatography eluting with (9:1) hexanes-ethyl acetate provided 6.98 g (47%) of title compound as a yellow crystalline solid. 1H NMR (CDCl3): δ 3.6 (s, 3H), 3.9 (s, 3H), 4.95 (s, 2H), 7.4-7.5 (m, 3H), 8.0 (m, 2H). the resulting brown mixture refluxed under nitrogen for 8 hours The mixture was partitioned between ethyl acetate and saturated NaHCO3 The organic layer was washed with water twice brine, then dried over anhydrous sodium sulfate concentrated in vacuo to give a brown oil Silica gel chromatography eluting with (9:1) hexanes-ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 46.0 g Methyl 4-methoxyacetoacetate were dissolved in 500 ml dichloromethane. 28.1 ml Sulfuryl chloride were added in one portion. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the resulting residue was dissolved in 300 ml ethyl acetate and washed with 100 ml water and 100 ml brine. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The resulting residue was purified by chromatography on silica gel with the eluent n-heptane:ethyl acetate=5:1=>2:1 to obtain 45.0 g 2-chloro-4-methoxy-3-oxo-butyric acid methyl ester as a yellow oil. The solvent was removed under reduced pressure the resulting residue was dissolved in 300 ml ethyl acetate washed with 100 ml water and 100 ml brine The organic layer was dried over MgSO4 the solvent removed under reduced pressure The resulting residue was purified by chromatography on silica gel with the eluent n-heptane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 46.0 g Methyl 4-methoxyacetoacetate were dissolved in 500 ml dichloromethane. 28.1 ml Sulfuryl chloride were added in one portion. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the resulting residue was dissolved in 300 ml ethyl acetate and washed with 100 ml water and 100 ml brine. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The resulting residue was purified by chromatography on silica gel with the eluent n-heptane:ethyl acetate=5:1=>2:1 to obtain 45.0 g 2-chloro-4-methoxy-3-oxo-butyric acid methyl ester as a yellow oil. The solvent was removed under reduced pressure the resulting residue was dissolved in 300 ml ethyl acetate washed with 100 ml water and 100 ml brine The organic layer was dried over MgSO4 the solvent removed under reduced pressure The resulting residue was purified by chromatography on silica gel with the eluent n-heptane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10.5 g 6-Trifluoromethyl-thionicotinamide (derived from 6-Trifluoromethyl-nicotinic acid according to the method described for 5-Chloromethyl-4-methyl-2-(1-methyl-cyclohexyl)-oxazole and 5-Chloromethyl-2-(4,4-difluoro-cyclohexyl)-4-methoxymethyl-thiazole) and 10.0 g 2-Chloro-4-methoxy-3-oxo-butyric acid methyl ester were dissolved in 100 ml ethanol and heated under reflux overnight. The cooled reaction mixture was evaporated under reduced pressure and the resulting residue was purified by RP-HPLC to obtain 1.9 g 4-Methoxymethyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carboxylic acid methyl ester. heated under reflux overnight The cooled reaction mixture was evaporated under reduced pressure the resulting residue was purified by RP-HPLC

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10.5 g 6-Trifluoromethyl-thionicotinamide (derived from 6-Trifluoromethyl-nicotinic acid according to the method described for 5-Chloromethyl-4-methyl-2-(1-methyl-cyclohexyl)-oxazole and 5-Chloromethyl-2-(4,4-difluoro-cyclohexyl)-4-methoxymethyl-thiazole) and 10.0 g 2-Chloro-4-methoxy-3-oxo-butyric acid methyl ester were dissolved in 100 ml ethanol and heated under reflux overnight. The cooled reaction mixture was evaporated under reduced pressure and the resulting residue was purified by RP-HPLC to obtain 1.9 g 4-Methoxymethyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carboxylic acid methyl ester. heated under reflux overnight The cooled reaction mixture was evaporated under reduced pressure the resulting residue was purified by RP-HPLC

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7.0 g 4,4-Difluoro-cyclohexanecarbothioic acid amide and 8.46 g 2-Chloro-4-methoxy-3-oxo-butyric acid methyl ester were dissolved in 70 ml ethanol and heated under reflux overnight. The cooled reaction mixture was evaporated under reduced pressure and the resulting residue was purified by silica chromatography with the eluent n-heptane:ethyl acetate=4:1=>2:1 to obtain 4.0 g 2-(4,4-Difluoro-cyclohexyl)-4-methoxymethyl-thiazole-5-carboxylic acid methyl ester as an oil. heated under reflux overnight The cooled reaction mixture was evaporated under reduced pressure the resulting residue was purified by silica chromatography with the eluent n-heptane