(1R)-3-(methylamino)-1-phenylpropan-1-ol

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

Procedure: A process according to claim 6 comprising the additional step, following all preceding steps, of reacting (R)-3-(methylamino)-1-phenylpropanol with a strong base followed by 4-chlorobenzotrifluoride to provide (R)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-N-methyl-3-phenyl-3-hydroxy-propylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (8) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit.133b mp 140°-141.5° C.; [α]23D-2.16° (c 1.62, MeOH); (lit.133b [α]23D-1.97° [c 1.00, MeOH]); [α]23D +7.08° (c 1.30, H2O); (lit⟦alpha⟧sup.23 D +10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) δ9.72 (br, s, 2H), 7.40-7.43 (d, J=8.7 Hz, 2H), 7.25-7.33 (m, 5H), 6.88-6.92 (d, J=8.7 Hz, 2H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1H), 3.12 (br, s, 2H), 2.55-2.62 (br, s, 3H), 2.42-2.52 (m, 2H); Anal. Calcd. for C17H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50. with cooling an orange solution resulted After cooling dilution with toluene, the mixture was washed with water the aqueous layer was separated extracted with toluene The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine dried over magnesium sulfate Concentration

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-N-methyl-3-phenyl-3-hydroxy-propylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (8) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit.133b mp 140°-141.5° C.; [α]23D-2.16° (c 1.62, MeOH); (lit.133b [α]23D-1.97° [c 1.00, MeOH]); [α]23D +7.08° (c 1.30, H2O); (lit⟦alpha⟧sup.23 D +10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) δ9.72 (br, s, 2H), 7.40-7.43 (d, J=8.7 Hz, 2H), 7.25-7.33 (m, 5H), 6.88-6.92 (d, J=8.7 Hz, 2H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1H), 3.12 (br, s, 2H), 2.55-2.62 (br, s, 3H), 2.42-2.52 (m, 2H); Anal. Calcd. for C17H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50. with cooling an orange solution resulted After cooling dilution with toluene, the mixture was washed with water the aqueous layer was separated extracted with toluene The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine dried over magnesium sulfate Concentration

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-N-methyl-3-phenyl-3-hydroxy-propylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (8) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit. mp 140°-141.5° C.; [α]23D -2.16° (c 1.62, MeOH); (lit⟦alpha⟧sup.23 D -1.97° [c 1.00, MeOH]); [α]23D +7.08° (c 1.30, H2O); (lit. [α]23D +10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) δ9.72 (br, s, 2 H), 7.40-7.43 (d, J=8.7 Hz, 2 H), 7.25-7.33 (m, 5 H), 6.88-6.92 (d, J=8.7 Hz, 2 H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1 H), 3.12 (br, s, 2 H), 2.55-2.62 (br, s, 3 H), 2.42-2.52 (m, 2 H); Anal. Calcd. for C17H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50. with cooling an orange solution resulted After cooling dilution with toluene, the mixture was washed with water the aqueous layer was separated extracted with toluene The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine dried over magnesium sulfate Concentration

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-N-methyl-3-phenyl-3-hydroxypropylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (s) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit.133b mp 140°-141.5° C.; [α]23D-2.16. (c 1.62, MeOH); (lit.133b [α]23D-1.97° [c 1.00, MeOH]); [α]23D+7.08. (c 1.30, H2O); (lit. [α]23D+10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) & 9.72 (br, s, 2H), 7.40-7.43 (d, J=8.7 Hz, 2H), 7.25-7.33 (m, 5H), 6.88-6.92 (d, J=8.7 Hz, 2H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1H), 3.12 (br, s, 2H), 2.55-2.62 (br, s, 3H), 2.42-2.52 (m, 2H); Anal. Calcd. for C17H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50. with cooling an orange solution resulted After cooling dilution with toluene, the mixture was washed with water the aqueous layer was separated extracted with toluene The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine dried over magnesium sulfate Concentration

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-N-methyl-3-phenyl-3-hydroxypropylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (s) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit.133b mp 140°-141.5° C.; [α]23D-2.16. (c 1.62, MeOH); (lit.133b [α]23D-1.97° [c 1.00, MeOH]); [α]23D+7.08. (c 1.30, H2O); (lit. [α]23D+10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) & 9.72 (br, s, 2H), 7.40-7.43 (d, J=8.7 Hz, 2H), 7.25-7.33 (m, 5H), 6.88-6.92 (d, J=8.7 Hz, 2H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1H), 3.12 (br, s, 2H), 2.55-2.62 (br, s, 3H), 2.42-2.52 (m, 2H); Anal. Calcd. for C17H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50. with cooling an orange solution resulted After cooling dilution with toluene, the mixture was washed with water the aqueous layer was separated extracted with toluene The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine dried over magnesium sulfate Concentration

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-N-methyl-3-phenyl-3-hydroxy-propylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over be magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (8) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit.133b mp 140°-141.5° C.; [α]23D -2.16° (c 1.62, MeOH); (lit.133b [α]23D -1.97° [c 1.00, MeOH]); [α]23D +7.08° (c 1.30, H2O); (lit. [α]23D +10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) δ9.72 (br, s, 2 H), 7.40-7.43 (d, J=8.7 Hz, 2 H), 7.25-7.33 (m, 5 H), 6.88-6.92 (d, J=8.7 Hz, 2 H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1 H), 3.12 (br, s, 2 H), 2.55-2.62 (br, s, 3 H), 2.42-2.52 (m, 2 H); Anal. Calcd. for C17 H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50. with cooling an orange solution resulted After cooling dilution with toluene, the mixture was washed with water the aqueous layer was separated extracted with toluene The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine dried Concentration

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-N-methyl-3-phenyl-3-hydroxy-propylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over be magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (8) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit.133b mp 140°-141.5° C.; [α]23D -2.16° (c 1.62, MeOH); (lit.133b [α]23D -1.97° [c 1.00, MeOH]); [α]23D +7.08° (c 1.30, H2O); (lit. [α]23D +10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) δ9.72 (br, s, 2 H), 7.40-7.43 (d, J=8.7 Hz, 2 H), 7.25-7.33 (m, 5 H), 6.88-6.92 (d, J=8.7 Hz, 2 H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1 H), 3.12 (br, s, 2 H), 2.55-2.62 (br, s, 3 H), 2.42-2.52 (m, 2 H); Anal. Calcd. for C17 H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50. with cooling an orange solution resulted After cooling dilution with toluene, the mixture was washed with water the aqueous layer was separated extracted with toluene The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine dried Concentration

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

Procedure: A process according to claim 6 comprising the additional step, following all preceding steps, of reacting (R)-3-(methylamino)-1-phenylpropanol with a strong base followed by 4-chlorobenzotrifluoride to provide (R)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-N-methyl-3-phenyl-3-hydroxy-propylamine (7) (1.23 g, 7.45 mmol) in dimethyl acetamide (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 90° C. for 1.5 h, and an orange solution resulted. To this solution was then added 4-chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100°-105° C. for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. Concentration provided (R)-fluoxetine as an orange oil (1.97 g, 86%). The oil was dissolved in ether and acidified with hydrogen chloride gas (pH=3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20° C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride (8) as a white powder (1.90 g, 75%): mp 140°-142° C. (lit.133b mp 140°-141.5° C.; [α]23D-2.16° (c 1.62, MeOH); (lit.133b [α]23D-1.97° [c 1.00, MeOH]); [α]23D +7.08° (c 1.30, H2O); (lit⟦alpha⟧sup.23 D +10.32° [c 1.00, H2O]); IR (KBr, CDCl3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-1; 1H NMR (CDCl3) δ9.72 (br, s, 2H), 7.40-7.43 (d, J=8.7 Hz, 2H), 7.25-7.33 (m, 5H), 6.88-6.92 (d, J=8.7 Hz, 2H), 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1H), 3.12 (br, s, 2H), 2.55-2.62 (br, s, 3H), 2.42-2.52 (m, 2H); Anal. Calcd. for C17H19ClF3NO: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50. with cooling an orange solution resulted After cooling dilution with toluene, the mixture was washed with water the aqueous layer was separated extracted with toluene The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine dried over magnesium sulfate Concentration

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

Procedure: The oily product of (R)-3-methoxymethylamino-1-phenyl-1-propanol obtained in example 2 was dissolved in 100 mL of methanol again with 1.2 g of Raney-nickel in a glass autoclave. The resulting solution was hydrogenated at 50° C. for 12 hours. Upon completion of hydrogenation, the reaction mixture was filtered and the solvent was removed under reduced pressure to obtain an objective compound as an oily compound (39.0 g, 96.5% by HPLC assay, 99% ee). The crude product was further purified by re-crystallization in toluene and heptane with optical purity as high as 100% ee. 1H NMR (400 MHz, CDCl3) δ (ppm)=1.7-1.8 (m, 1H), 1.8-1.9 (m, 1H), 2.5 (s, 3H), 2.8-2.9 (m, 2H), 4.9 (dd, J=3, 8.6 Hz, 1H), 7.3-7.4 (m, 5H). Upon completion of hydrogenation, the reaction mixture was filtered the solvent was removed under reduced pressure to obtain an objective compound as an oily compound (39.0 g, 96.5% by HPLC assay, 99% ee) The crude product was further purified by re-crystallization in toluene

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

Procedure: A process according to claim 6 comprising the additional step, following all preceding steps, of reacting (R)-3-(methylamino)-1-phenylpropanol with a strong base followed by 4-chlorobenzotrifluoride to provide (R)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine.