ethyl 4,4,4-trifluorobut-2-ynoate

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

Procedure: A mixture of ethyl 4,4,4-trifluoro-2-(triphenylphosphoranylidene)acetoacetate (270 g, 617 mmol) and potassium carbonate (54 g, 490 mmol) is heated from 160° C. to 225° C. in 3 h at 2-3 mbar vacuum. The title compound is distilled and recovered in a cold trap to yield the title compound (85 g, 83%) as a slightly yellow oil. ES/MS m/e 167 (M+1). is heated from 160° C. to 225° C. in 3 h at 2-3 mbar vacuum The title compound is distilled recovered in a cold trap

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-Azido-1,3-dichloro-benzene (25.0 g, 132.9 mmol) and 4,4,4-trifluoro-but-2-ynoic acid ethyl ester (26.5 g, 159.6 mmol) in toluene (30 mL) are heated at 80° C. for 18 h. A large exotherm is observed at 25 minutes. The reaction is removed from heat until exotherm subsides. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction mixture is concentrated under reduced pressure to 51 g of crude material and purified via column chromatography using a gradient of 35-60% DCM in Hexanes to yield the title compound (28 g, 59%). ES/MS m/e 353.0 (M+1). The reaction is removed from heat until exotherm subsides The reaction mixture is concentrated under reduced pressure to 51 g of crude material purified via column chromatography

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

Procedure: To a solution of diazomethane (0.781 g—generated from DIAZALD® (3.99 g) in diethyl ether (63 ml)), cooled by an ice/water bath, was added ethyl 4,4,4-trifluoro-2-butynoate (3.09 g) dropwise over 1 min. The cooling bath was removed and the mixture was stirred for 30 min when the solvent was removed under reduced pressure. The crude product was combined with the crude product from a similar experiment that was performed with 1,4 dioxane (5 ml) and n-pentane (15 ml) as the solvent and purified by column chromatography on silica gel to give a white solid. To a solution of a portion of this solid (100 mg) in 1,4-dioxane (2 ml) was added 2M hydrochloric acid (3 ml) and the mixture heated at reflux for 18 h, then concentrated hydrochloric acid (2 drops) was added and the mixture heated at reflux for a further 48 h. The mixture was concentrated in vacuo and the residue purified by mass directed preparative HPLC (Method A), to give the title compound, as a white solid (19 mg). The cooling bath was removed was removed under reduced pressure purified by column chromatography on silica gel to give a white solid the mixture heated at reflux for 18 h the mixture heated at reflux for a further 48 h The mixture was concentrated in vacuo the residue purified by mass

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

Procedure: To a solution of diazomethane (0.781 g—generated from DIAZALD® (3.99 g) in diethyl ether (63 ml)), cooled by an ice/water bath, was added ethyl 4,4,4-trifluoro-2-butynoate (3.09 g) dropwise over 1 min. The cooling bath was removed and the mixture was stirred for 30 min when the solvent was removed under reduced pressure. The crude product was combined with the crude product from a similar experiment that was performed with 1,4 dioxane (5 ml) and n-pentane (15 ml) as the solvent and purified by column chromatography on silica gel to give a white solid. To a solution of a portion of this solid (100 mg) in 1,4-dioxane (2 ml) was added 2M hydrochloric acid (3 ml) and the mixture heated at reflux for 18 h, then concentrated hydrochloric acid (2 drops) was added and the mixture heated at reflux for a further 48 h. The mixture was concentrated in vacuo and the residue purified by mass directed preparative HPLC (Method A), to give the title compound, as a white solid (19 mg). The cooling bath was removed was removed under reduced pressure purified by column chromatography on silica gel to give a white solid the mixture heated at reflux for 18 h the mixture heated at reflux for a further 48 h The mixture was concentrated in vacuo the residue purified by mass

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (165 mg, 0.602 mmol) in ethanol (6 mL) was added ethyl 4,4,4-trifluoro-2-butynoate (100 mg, 0.602 mmol). The reaction mixture was heated in a microwave oven at 170° C. for 30 mins. Solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 1-10% EtOH/CH2Cl2) to afford 60 mg of 2-(4-cyclohexyl-phenoxymethyl)-5-trifluoromethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as an off-white solid. Solvent was removed under vacuum the residue purified via flash column chromatography (silica gel, 1-10% EtOH/CH2Cl2)

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

Procedure: A solution of 2.1 g (38 mmol) of KOH in 20 ml of water and then 6.7 g (30 mmol) of 1-aminopyridinium iodide are added to a solution of 2.5 g (15 mmol) of ethyl 4,4,4-trifluorobut-2-ynoate in 25 ml of dichloromethane. After stirring at ambient temperature for 5 h, water is added and the reaction medium is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 2.8 g (73%) of ethyl 2-trifluoromethylpyrazolo[1,5-α]pyridine-3-carboxylate are obtained in the form of a yellow solid. the reaction medium is extracted with dichloromethane The organic phase is washed with water dried over magnesium sulfate filtered concentrated The residue obtained is purified by chromatography on silica gel, elution

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

Procedure: A mixture of 2.1 g (37.6 mmol) of potassium hydroxide and 6.7 g (30.1 mmol) of aminopyridinium iodide in 20 ml of water is added to a solution of 2.5 g (15.1 mmol) of ethyl 4,4,4-trifluorobut-2-ynoate in 25 ml of dichloromethane. After stirring for 5 h at ambient temperature, water is added and the mixture is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated to dryness. The crude product is purified by chromatography over silica gel eluted with an 80/20 heptane/ethyl acetate mixture. 2.8 g (73%) of ethyl 2-trifluoromethylpyrazolo[1,5-a]pyridine-3-carboxylate are obtained in the form of a yellow solid. the mixture is extracted with dichloromethane The organic phase is washed with water dried over magnesium sulphate filtered concentrated to dryness The crude product is purified by chromatography over silica gel eluted with an 80/20 heptane/ethyl acetate mixture

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

Procedure: A mixture of ethyl 4,4,4-trifluoro-2-(triphenylphosphoranylidene)acetoacetate (270 g, 617 mmol) and potassium carbonate (54 g, 490 mmol) is heated from 160° C. to 225° C. in 3 h at 2-3 mbar vacuum. The title compound is distilled and recovered in a cold trap to yield the title compound (85 g, 83%) as a slightly yellow oil. ES/MS m/e 167 (M+1). is heated from 160° C. to 225° C. in 3 h at 2-3 mbar vacuum The title compound is distilled recovered in a cold trap

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-Azido-1,3-dichloro-benzene (25.0 g, 132.9 mmol) and 4,4,4-trifluoro-but-2-ynoic acid ethyl ester (26.5 g, 159.6 mmol) in toluene (30 mL) are heated at 80° C. for 18 h. A large exotherm is observed at 25 minutes. The reaction is removed from heat until exotherm subsides. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction mixture is concentrated under reduced pressure to 51 g of crude material and purified via column chromatography using a gradient of 35-60% DCM in Hexanes to yield the title compound (28 g, 59%). ES/MS m/e 353.0 (M+1). The reaction is removed from heat until exotherm subsides The reaction mixture is concentrated under reduced pressure to 51 g of crude material purified via column chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-Azido-1,3-dichloro-benzene (25.0 g, 132.9 mmol) and 4,4,4-trifluoro-but-2-ynoic acid ethyl ester (26.5 g, 159.6 mmol) in toluene (30 mL) are heated at 80° C. for 18 h. A large exotherm is observed at 25 minutes. The reaction is removed from heat until exotherm subsides. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction mixture is concentrated under reduced pressure to 51 g of crude material and purified via column chromatography using a gradient of 35-60% DCM in Hexanes to yield the title compound (28 g, 59%). ES/MS m/e 353.0 (M+1). The reaction is removed from heat until exotherm subsides The reaction mixture is concentrated under reduced pressure to 51 g of crude material purified via column chromatography

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

Procedure: To a solution of diazomethane (0.781 g—generated from DIAZALD® (3.99 g) in diethyl ether (63 ml)), cooled by an ice/water bath, was added ethyl 4,4,4-trifluoro-2-butynoate (3.09 g) dropwise over 1 min. The cooling bath was removed and the mixture was stirred for 30 min when the solvent was removed under reduced pressure. The crude product was combined with the crude product from a similar experiment that was performed with 1,4 dioxane (5 ml) and n-pentane (15 ml) as the solvent and purified by column chromatography on silica gel to give a white solid. To a solution of a portion of this solid (100 mg) in 1,4-dioxane (2 ml) was added 2M hydrochloric acid (3 ml) and the mixture heated at reflux for 18 h, then concentrated hydrochloric acid (2 drops) was added and the mixture heated at reflux for a further 48 h. The mixture was concentrated in vacuo and the residue purified by mass directed preparative HPLC (Method A), to give the title compound, as a white solid (19 mg). The cooling bath was removed was removed under reduced pressure purified by column chromatography on silica gel to give a white solid the mixture heated at reflux for 18 h the mixture heated at reflux for a further 48 h The mixture was concentrated in vacuo the residue purified by mass

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (165 mg, 0.602 mmol) in ethanol (6 mL) was added ethyl 4,4,4-trifluoro-2-butynoate (100 mg, 0.602 mmol). The reaction mixture was heated in a microwave oven at 170° C. for 30 mins. Solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 1-10% EtOH/CH2Cl2) to afford 60 mg of 2-(4-cyclohexyl-phenoxymethyl)-5-trifluoromethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as an off-white solid. Solvent was removed under vacuum the residue purified via flash column chromatography (silica gel, 1-10% EtOH/CH2Cl2)