1-(3,4,5-trifluorophenyl)ethanone

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

Procedure: 3,4,5-Trifluorophenol (5.0 g, 0.034 mol), which was obtained by reacting a Grignard reagent of 1-bromo-3,4,5-trifluorobenzene with acetyl chloride, oxidizing the resulting 1-acetyl-3,4,5-trifluorobenzene with a peracid to obtain 3,4,5-trifluorophenyl acetate and subjecting this acetate to hydrolysis reaction, was dissolved in dry pyridine (10 ml), followed by gradually adding trans-4-propyl-cyclohexylcarbonyl chloride (6.4 g), allowing the resulting reaction solution to stand at 50° C. for 3 hours, adding water (100 ml) to the reaction solution, extracting the resulting deposited oily substance with n-heptane (30 ml), washing the n-heptane solution with a dilute hydrochloric acid aqueous solution and then with a dilute alkali aqueous solution, further washing with water till the washing water became neutral, drying the n-heptane solution over anhydrous sodium sulfate, distilling off n-heptane and recrystallizing the resulting oily substance from ethyl alcohol to obtain 3,4,5-trifluorophenyltrans-4-propylcyclohexyl carboxylate (6.5 g).C-I: 4.5° C.

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

Procedure: Using the method described in Example 30 by employing [1-(3,4,5-trifluorophenyl)vinyl]pyrrolidine (freshly prepared before use from 3,4,5-trifluoro acetophenone (Oakwood Products Inc.), pyrrolidine and TiCl4 (1.58 g, 6.96 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.40 g, 6.96 mmol), N,N-diisopropylethylamine (1.2 mL, 6.96 mmol), piperidine (1.1 mL, 11.1 mmol), NEt3 (1.1 mL) and SnCl2 (21 mL of a 2 M soln in DMF). In this example the 2 M SnCl2 solution was added to the reaction mixture at 140° C. Heating was then discontinued and the mixture was allowed to cool to room temperature. The mixture was stirred at room temperature for an additional 48 h. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give 620 mg (26%) of 2-methyl-4-piperidyl-6-(3,4,5-trifluoro phenyl)pyrrolo[3,2-d]pyrimidine as a beige colored gummy solid. This compound (621 mg, 1.80 mmol) was dissolved in 3:1 EtOAc/MeOH (50 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.80 mL, 1.80 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 426 mg (16%) of the title compound as a white colored fluffy solid. Mp: >280° C. 1H NMR (DMSO-d6; 500 MHz): δ 1.71 (br s, 6), 2.58 (s, 3), 4.07 (s, 4), 7.07 (s, 1), 8.14 (m, 2), 12.04 (s, 1), 14.45 (s, 1). MS m/z: 347 (M+1 for free base). Anal. Calcd for C18H17F3N4.HCl.0.5H2O: C, 55.23; H, 4.88; N, 14.32; Cl, 9.06. Found: C, 55.23; H, 4.86; N, 14.11; Cl, 9.06. was added to the reaction mixture at 140° C Heating The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant

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

Procedure: Using the method described in Example 30 by employing [1-(3,4,5-trifluorophenyl)vinyl]pyrrolidine (freshly prepared before use from 3,4,5-trifluoro acetophenone (Oakwood Products Inc.), pyrrolidine and TiCl4 (1.58 g, 6.96 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.40 g, 6.96 mmol), N,N-diisopropylethylamine (1.2 mL, 6.96 mmol), piperidine (1.1 mL, 11.1 mmol), NEt3 (1.1 mL) and SnCl2 (21 mL of a 2 M soln in DMF). In this example the 2 M SnCl2 solution was added to the reaction mixture at 140° C. Heating was then discontinued and the mixture was allowed to cool to room temperature. The mixture was stirred at room temperature for an additional 48 h. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give 620 mg (26%) of 2-methyl-4-piperidyl-6-(3,4,5-trifluoro phenyl)pyrrolo[3,2-d]pyrimidine as a beige colored gummy solid. This compound (621 mg, 1.80 mmol) was dissolved in 3:1 EtOAc/MeOH (50 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.80 mL, 1.80 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 426 mg (16%) of the title compound as a white colored fluffy solid. Mp: >280° C. 1H NMR (DMSO-d6; 500 MHz): δ 1.71 (br s, 6), 2.58 (s, 3), 4.07 (s, 4), 7.07 (s, 1), 8.14 (m, 2), 12.04 (s, 1), 14.45 (s, 1). MS m/z: 347 (M+1 for free base). Anal. Calcd for C18H17F3N4.HCl.0.5H2O: C, 55.23; H, 4.88; N, 14.32; Cl, 9.06. Found: C, 55.23; H, 4.86; N, 14.11; Cl, 9.06. was added to the reaction mixture at 140° C Heating The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant

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

Procedure: The 3,4,5-triflouroacetophenone (9.50 g, 54.6 mmol) and sodium thiomethoxide (4.60 g) were mixed together in acetonitrile (80 mL). The solution was stirred for 2 hour at ambient temperature. Solvent was removed in vacuo and the residue dissolved in ethyl acetate. The solution was extracted with water (2×100 mL), saturated ammonium chloride (2×100 mL) and dried over sodium sulfate. Solvent was removed in vacuo to yield 1-[3,5-difluoro-4-(methyl-thio)phenyl]ethanone as a yellow oil (8.08 g, 73%). 1H NMR (CDCl3/300 MHz) 7.46-7.43 (m, 2H), 2.58 (s, 3H), 2.56 (t, 3H, J=1). ESHRMS m/z 203.0357 (M+H+, Calcd 203.0342). Solvent was removed in vacuo the residue dissolved in ethyl acetate The solution was extracted with water (2×100 mL), saturated ammonium chloride (2×100 mL) dried over sodium sulfate Solvent was removed in vacuo

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

Procedure: The 3,4,5-triflouroacetophenone (9.50 g, 54.6 mmol) and sodium thiomethoxide (4.60 g) were mixed together in acetonitrile (80 mL). The solution was stirred for 2 hour at ambient temperature. Solvent was removed in vacuo and the residue dissolved in ethyl acetate. The solution was extracted with water (2×100 mL), saturated ammonium chloride (2×100 mL) and dried over sodium sulfate. Solvent was removed in vacuo to yield 1-[3,5-difluoro-4-(methyl-thio)phenyl]ethanone as a yellow oil (8.08 g, 73%). 1H NMR (CDCl3/300 MHz) 7.46-7.43 (m, 2H), 2.58 (s, 3H), 2.56 (t, 3H, J=1). ESHRMS m/z 203.0357 (M+H+, Calcd 203.0342). Solvent was removed in vacuo the residue dissolved in ethyl acetate The solution was extracted with water (2×100 mL), saturated ammonium chloride (2×100 mL) dried over sodium sulfate Solvent was removed in vacuo

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

Procedure: 20 g of 3,4,5-trifluoroacetophenone are converted into the pyridazinone in accordance with GWP 1.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium tert.-butoxide (1.12 g, 10.0 mmol) was added to a solution of 1-(3,4,5-trifluoro-phenyl)-ethanone (1.74 g, 10.0 mmol) and diethyl oxalate (1.49 mL, 11.0 mmol) in diethyl ether (20 mL) cooled to 0° C. The heterogenous mixture was stirred for 15 min at 0° C. followed by 15 h at 20° C. The mixture was partitioned between 3 N hydrochloric acid (20 mL) and diethyl ether (50 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure and the residual oil was crystallized from diethyl ether/heptane to give the title compound as a white solid. followed by 15 h at 20° C The mixture was partitioned between 3 N hydrochloric acid (20 mL) and diethyl ether (50 mL) The organic layer was washed with brine (20 mL) dried over sodium sulfate evaporated under reduced pressure the residual oil was crystallized from diethyl ether/heptane

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

Procedure: The 3,4,5-triflouroacetophenone (9.50 g, 54.6 mmol) and sodium thiomethoxide (4.60 g) were mixed together in acetonitrile (80 mL). The solution was stirred for 2 hour at ambient temperature. Solvent was removed in vacuo and the residue dissolved in ethyl acetate. The solution was extracted with water (2×100 mL), saturated ammonium chloride (2×100 mL) and dried over sodium sulfate. Solvent was removed in vacuo to yield 1-[3,5-difluoro-4-(methyl-thio)phenyl]ethanone as a yellow oil (8.08 g, 73%). 1H NMR (CDCl3/300 MHz) 7.46-7.43 (m, 2H), 2.58 (s, 3H), 2.56 (t, 3H, J=1). ESHRMS m/z 203.0357 (M+H+, Calcd 203.0342). Solvent was removed in vacuo the residue dissolved in ethyl acetate The solution was extracted with water (2×100 mL), saturated ammonium chloride (2×100 mL) dried over sodium sulfate Solvent was removed in vacuo

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

Procedure: To a solution of (+)-DIP-chloride (11.8 g) in THF (200 ml) cooled to −30° C., 3,4,5-trifluoroacetophenone (5.0 g) [CAS 220141-73-1] was added dropwise in a nitrogen atmosphere. The reaction solution was stirred at the same temperature for five hours and at room temperature at one hour, and then THF was evaporated under reduced pressure. 6.5 ml of diethanolamine was added dropwise to a solution of the resulting residue in diethyl ether (150 ml), and the reaction solution was stirred at room temperature overnight. The insoluble matter was removed by filtration, and then the solvent was evaporated. Hexane was added to the resulting residue, and the insoluble matter was removed by filtration again. The filtrate was purified by silica gel column chromatography (heptane:ethyl acetate=19:1 to 4:1) to obtain 3.69 g of the title compound. THF was evaporated under reduced pressure 6.5 ml of diethanolamine was added dropwise to a solution of the resulting residue in diethyl ether (150 ml) the reaction solution was stirred at room temperature overnight The insoluble matter was removed by filtration the solvent was evaporated Hexane was added to the resulting residue the insoluble matter was removed by filtration again The filtrate was purified by silica gel column chromatography (heptane:ethyl acetate=19:1 to 4:1)

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

Procedure: A mixture of 3,4,5-trifluoroacetophenone (2.0 g), ethanolamine (2.0 g), and toluene (20 mL) was heated under reflux in a Dean-Stark apparatus for 2.5 hours. The reaction solution was concentrated under reduced pressure, and then the residue was diluted with ethanol (30 mL) and sodium borohydride (1.0 g) was added under ice-cooling. The mixture was stirred at room temperature for three hours and then diluted with a 2 N sodium hydroxide solution and chloroform. Thereafter, the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (chloroform:methanol=50:1 to 5:1) to obtain 860 mg of the title compound. was heated under reflux in a Dean-Stark apparatus for 2.5 hours The reaction solution was concentrated under reduced pressure the residue was diluted with ethanol (30 mL) and sodium borohydride (1.0 g) was added under ice- cooling diluted with a 2 N sodium hydroxide solution and chloroform Thereafter, the organic layer was separated The organic layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by column chromatography

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

Procedure: Using the method described in Example 30 by employing [1-(3,4,5-trifluorophenyl)vinyl]pyrrolidine (freshly prepared before use from 3,4,5-trifluoro acetophenone (Oakwood Products Inc.), pyrrolidine and TiCl4 (1.58 g, 6.96 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.40 g, 6.96 mmol), N,N-diisopropylethylamine (1.2 mL, 6.96 mmol), piperidine (1.1 mL, 11.1 mmol), NEt3 (1.1 mL) and SnCl2 (21 mL of a 2 M soln in DMF). In this example the 2 M SnCl2 solution was added to the reaction mixture at 140° C. Heating was then discontinued and the mixture was allowed to cool to room temperature. The mixture was stirred at room temperature for an additional 48 h. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give 620 mg (26%) of 2-methyl-4-piperidyl-6-(3,4,5-trifluorophenyl)pyrrolo[3,2-d]pyrimidine as a beige colored gummy solid. This compound (621 mg, 1.80 mmol) was dissolved in 3:1 EtOAc/MeOH (50 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.80 mL, 1.80 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 426 mg (16%) of the title compound as a white colored fluffy solid. Mp: >280° C. 1H HMR (DMSO-d6; 500 MHz): δ 1.71 (br s, 6), 2.58 (s, 3), 4.07 (s, 4), 7.07 (s, 1), 8.14 (m, 2), 12.04 (s, 1), 14.45 (s, 1). MS m/z: 347 (M+1 for free base). Anal. Calcd for C18H17F3N4.HCl.0.5H2O: C, 55.23; H, 4.88; N, 14.32; Cl, 9.06. Found: C, 55.23; H, 4.86; N, 14.11; Cl, 9.06. was added to the reaction mixture at 140° C Heating The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant

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

Procedure: 3,4,5-Trifluorophenol (5.0 g, 0.034 mol), which was obtained by reacting a Grignard reagent of 1-bromo-3,4,5-trifluorobenzene with acetyl chloride, oxidizing the resulting 1-acetyl-3,4,5-trifluorobenzene with a peracid to obtain 3,4,5-trifluorophenyl acetate and subjecting this acetate to hydrolysis reaction, was dissolved in dry pyridine (10 ml), followed by gradually adding trans-4-propyl-cyclohexylcarbonyl chloride (6.4 g), allowing the resulting reaction solution to stand at 50° C. for 3 hours, adding water (100 ml) to the reaction solution, extracting the resulting deposited oily substance with n-heptane (30 ml), washing the n-heptane solution with a dilute hydrochloric acid aqueous solution and then with a dilute alkali aqueous solution, further washing with water till the washing water became neutral, drying the n-heptane solution over anhydrous sodium sulfate, distilling off n-heptane and recrystallizing the resulting oily substance from ethyl alcohol to obtain 3,4,5-trifluorophenyltrans-4-propylcyclohexyl carboxylate (6.5 g).C-I: 4.5° C.