(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride

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

Procedure: To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (0.10 g, 0.44 mmol) and dry methylene chloride (1.5 mL). The mixture was cooled in an ice bath and triethylamine (0.12 mL, 0.87 mmol) was added followed by (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol). The mixture was stirred for 2 hours at which point TLC showed the reaction to be incomplete. More (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol) was added and the reaction was allowed to stir 1 hour at room temperature. The mixture was diluted with methylene chloride, washed once with 1N HCl, once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride to give a clear oil, 5-methyl-3-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyl oxymethyl)-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, for which a yield was not determined. 1H-NMR (300 MHz, CD3COCD3) c (ppm): 2.38 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 4.10 (m, 1H), 4.48 (dd, 1H), 4.65 (m, 2H), 4.86 (m, 1H) 6.78 (d, 1H) 7.47 (m, 5H), 7.60 (d, 1H); 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −72.89 (s); both 1H- and 19F-NMR indicate the presence of only one stereo- and regioisomer; TLC: Rf=0.62 (1:1 ethyl acetate/hexane). To a round bottom flask equipped The mixture was cooled in an ice bath The mixture was stirred for 2 hours at which point TLC the reaction to stir 1 hour at room temperature washed once with 1N HCl, once with saturated sodium bicarbonate dried over magnesium sulfate filtered evaporated The residue was chromatographed on silica gel eluting with methylene chloride

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

Procedure: The resulting product was esterified with (R)α-methoxy-α-trifluoromethylphenylacetyl chloride, and the ester was analyzed by HPLC. From the area ratio of the chromatogram, the optical yield of the product was found to be 97.2% ee.

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

Procedure: To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (0.10 g, 0.44 mmol) and dry methylene chloride (1.5 mL). The mixture was cooled in an ice bath and triethylamine (0.12 mL, 0.87 mmol) was added followed by (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol). The mixture was stirred for 2 hours at which point TLC showed the reaction to be incomplete. More (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol) was added and the reaction was allowed to stir 1 hour at room temperature. The mixture was diluted with methylene chloride, washed once with 1N HCl, once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride to give a clear oil, 5-methyl-3-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyloxymethyl)-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, for which a yield was not determined. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.38 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 4.10 (m, 1H), 4.48 (dd, 1H), 4.65 (m, 2H), 4.86 (m, 1H) 6.78 (d, 1H) 7.47 (m, 5H), 7.60 (d, 1H); 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −72.89 (s); both 1H- and 19F-NMR indicate the presence of only one stereo- and regioisomer; TLC: Rf=0.62 (1:1 ethyl acetate/hexane). To a round bottom flask equipped The mixture was cooled in an ice bath The mixture was stirred for 2 hours at which point TLC the reaction to stir 1 hour at room temperature washed once with 1N HCl, once with saturated sodium bicarbonate dried over magnesium sulfate filtered evaporated The residue was chromatographed on silica gel eluting with methylene chloride

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

Procedure: To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (0.10 g, 0.44 mmol) and dry methylene chloride (1.5 mL). The mixture was cooled in an ice bath and triethylamine (0.12 mL, 0.87 mmol) was added followed by (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol). The mixture was stirred for 2 hours at which point TLC showed the reaction to be incomplete. More (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol) was added and the reaction was allowed to stir 1 hour at room temperature. The mixture was diluted with methylene chloride, washed once with 1N HCl, once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride to give a clear oil, 5-methyl 3-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyloxymethyl)-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, for which a yield was not determined. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.38 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 4.10 (m, 1H), 4.48 (dd, 1H), 4.65 (m, 2H), 4.86 (m, 1H) 6.78 (d, 1H) 7.47 (m, 5H), 7.60 (d, 1H); 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −72.89 (s); both 1H- and 19F-NMR indicate the presence of only one stereo- and regioisomer; TLC: Rf=0.62 (1:1 ethyl acetate/hexane). To a round bottom flask equipped The mixture was cooled in an ice bath The mixture was stirred for 2 hours at which point TLC the reaction to stir 1 hour at room temperature washed once with 1N HCl, once with saturated sodium bicarbonate dried over magnesium sulfate filtered evaporated The residue was chromatographed on silica gel eluting with methylene chloride

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

Procedure: To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (0.10 g, 0.44 mmol) and dry methylene chloride (1.5 mL). The mixture was cooled in an ice bath and triethylamine (0.12 mL, 0.87 mmol) was added followed by (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol). The mixture was stirred for 2 hours at which point TLC showed the reaction to be incomplete. More (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol) was added and the reaction was allowed to stir 1 hour at room temperature. The mixture was diluted with methylene chloride, washed once with 1N HCl, once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride to give a clear oil, 5-methyl 3-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyloxymethyl)-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, for which a yield was not determined. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.38 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 4.10 (m, 1H), 4.48 (dd, 1H), 4.65 (m, 2H), 4.86 (m, 1H) 6.78 (d, 1H) 7.47 (m, 5H), 7.60 (d, 1H); 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −72.89 (s); both 1H- and 19F-NMR indicate the presence of only one stereo- and regioisomer; TLC: Rf=0.62 (1:1 ethyl acetate/hexane). To a round bottom flask equipped The mixture was cooled in an ice bath The mixture was stirred for 2 hours at which point TLC the reaction to stir 1 hour at room temperature washed once with 1N HCl, once with saturated sodium bicarbonate dried over magnesium sulfate filtered evaporated The residue was chromatographed on silica gel eluting with methylene chloride

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

Procedure: 2-Amino-4-(4-octylphenyl)butanol (10 mg), N,N-dimethyl-p-aminopyridine (17.5 mg), anhydrous triethylamine (11.4 μl) and anhydrous methylene chloride (1 ml) were mixed and the mixture was stirred under a nitrogen atmosphere at room temperature. Thereto was added (R)-α-methoxy-α-trifluoromethylphenylacetyl chloride (16.8 μl) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer chromatography (eluent; chloroform:methanol=9:1) to give the two diastereomer mixtures. Moreover, the mixture was purified by high performance liquid chromatography (eluent; methanol:water=88:12, flow rate; 8.0 ml /minute) to give the subject oily substance (9.8 mg) of 67.8 minutes at retention time and the subject oily substance (9.6 mg) of 71.6 minutes at retention time. the mixture was stirred at room temperature for 10 hours The reaction mixture was concentrated under reduced pressure the residue obtained was purified by thin layer chromatography (eluent; chloroform:methanol=9:1) to give the two diastereomer mixtures Moreover, the mixture was purified by high performance liquid chromatography (eluent; methanol:water=88:12, flow rate; 8.0 ml /minute) to give the subject oily substance (9.8 mg) of 67.8 minutes at retention time the subject oily substance (9.6 mg) of 71.6 minutes

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

Procedure: 2-Amino-4-(4-octylphenyl)butanol (10 mg), N,N-dimethyl-p-aminopyridine (17.5 mg), anhydrous triethylamine (11.4 μl) and anhydrous methylene chloride (1 ml) were mixed and the mixture was stirred under a nitrogen atmosphere at room temperature. Thereto was added (R)-α-methoxy-α-trifluoromethylphenylacetyl chloride (16.8 μl) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer chromatography (eluent; chloroform:methanol=9:1) to give the two diastereomer mixtures. Moreover, the mixture was purified by high performance liquid chromatography (eluent; methanol:water=88:12, flow rate; 8.0 ml /minute) to give the subject oily substance (9.8 mg) of 67.8 minutes at retention time and the subject oily substance (9.6 mg) of 71.6 minutes at retention time. the mixture was stirred at room temperature for 10 hours The reaction mixture was concentrated under reduced pressure the residue obtained was purified by thin layer chromatography (eluent; chloroform:methanol=9:1) to give the two diastereomer mixtures Moreover, the mixture was purified by high performance liquid chromatography (eluent; methanol:water=88:12, flow rate; 8.0 ml /minute) to give the subject oily substance (9.8 mg) of 67.8 minutes at retention time the subject oily substance (9.6 mg) of 71.6 minutes

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

Procedure: To a solution of 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (368 mg, 0.94 mmol), prepared using procedures similar to those described in Reference 5, in dichloromethane (5 mL) was added DMAP (115 mg, 0.94 mmol) and the resulting solution was cooled to 0° C. (R)-(−)-α-Methoxy-α-trifluoromethylphenylacetyl chloride (105 μL, 0.56 mmol) was added to the solution by syringe and the mixture was allowed to warm to room temperature then stirred an additional 12 hours. The solution was then partitioned with saturated aqueous sodium bicarbonate and the organic phase dried over anhydrous magnesium sulfate then filtered and concentrated to an oily residue. Silica gel flash chromatography using hexanes:ethyl acetate 3:1 as eluent afforded the less polar 1,1-dimethylethyl(2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (27.5 mg, 5% yield), the more polar 1,1-dimethylethyl(2S)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (105 mg, 19% yield) and starting material (253 mg, 69% recovery). was added to the solution by syringe The solution was then partitioned with saturated aqueous sodium bicarbonate the organic phase dried over anhydrous magnesium sulfate then filtered concentrated to an oily residue

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

Procedure: To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (0.10 g, 0.44 mmol) and dry methylene chloride (1.5 mL). The mixture was cooled in an ice bath and triethylamine (0.12 mL, 0.87 mmol) was added followed by (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol). The mixture was stirred for 2 hours at which point TLC showed the reaction to be incomplete. More (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol) was added and the reaction was allowed to stir 1 hour at room temperature. The mixture was diluted with methylene chloride, washed once with 1N HCl, once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride to give a clear oil, 5-methyl-3-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyl oxymethyl)-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, for which a yield was not determined. 1H-NMR (300 MHz, CD3COCD3) c (ppm): 2.38 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 4.10 (m, 1H), 4.48 (dd, 1H), 4.65 (m, 2H), 4.86 (m, 1H) 6.78 (d, 1H) 7.47 (m, 5H), 7.60 (d, 1H); 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −72.89 (s); both 1H- and 19F-NMR indicate the presence of only one stereo- and regioisomer; TLC: Rf=0.62 (1:1 ethyl acetate/hexane). To a round bottom flask equipped The mixture was cooled in an ice bath The mixture was stirred for 2 hours at which point TLC the reaction to stir 1 hour at room temperature washed once with 1N HCl, once with saturated sodium bicarbonate dried over magnesium sulfate filtered evaporated The residue was chromatographed on silica gel eluting with methylene chloride

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

Procedure: To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (0.10 g, 0.44 mmol) and dry methylene chloride (1.5 mL). The mixture was cooled in an ice bath and triethylamine (0.12 mL, 0.87 mmol) was added followed by (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol). The mixture was stirred for 2 hours at which point TLC showed the reaction to be incomplete. More (R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.09 mL, 0.48 mmol) was added and the reaction was allowed to stir 1 hour at room temperature. The mixture was diluted with methylene chloride, washed once with 1N HCl, once with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride to give a clear oil, 5-methyl-3-(3,3,3-trifluoro-2-methoxy-2-phenyl-propionyl oxymethyl)-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, for which a yield was not determined. 1H-NMR (300 MHz, CD3COCD3) c (ppm): 2.38 (s, 3H), 3.58 (s, 3H), 3.81 (s, 3H), 4.10 (m, 1H), 4.48 (dd, 1H), 4.65 (m, 2H), 4.86 (m, 1H) 6.78 (d, 1H) 7.47 (m, 5H), 7.60 (d, 1H); 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −72.89 (s); both 1H- and 19F-NMR indicate the presence of only one stereo- and regioisomer; TLC: Rf=0.62 (1:1 ethyl acetate/hexane). To a round bottom flask equipped The mixture was cooled in an ice bath The mixture was stirred for 2 hours at which point TLC the reaction to stir 1 hour at room temperature washed once with 1N HCl, once with saturated sodium bicarbonate dried over magnesium sulfate filtered evaporated The residue was chromatographed on silica gel eluting with methylene chloride

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

Procedure: The resulting product was esterified with (R)α-methoxy-α-trifluoromethylphenylacetyl chloride, and the ester was analyzed by HPLC. From the area ratio of the chromatogram, the optical yield of the product was found to be 97.2% ee.

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

Procedure: The resulting product was esterified with (R)α-methoxy-α-trifluoromethylphenylacetyl chloride, and the ester was analyzed by HPLC. From the area ratio of the chromatogram, the optical yield of the product was found to be 97.2% ee.