Benzeneethanol, beta-amino-4-fluoro-, (betaR)- (9CI)

To a stirred solution of lithium aluminium hydride (1.0 M in THF, 11.9 ml, 11.9 mmol) at0 C was added 4- (R)-fluorophenylglycine (1.0 g, 5.9 mmol) portion wise over 1 hour. The mixture was stirred at room temperature for 16 hours. Water (0.45 ml), 4 NNaOH (0.45 ml) and water (1.34 ml) was added to the mixture and the mixture was stirred for 10 minutes before being filtered. The filtrate was concentrated to give a yellow residue. Flash chromatography(CombiFlash, CH2Cl2/MeOH/NH3 = 90/10/1) gave productas a white solid (800 mg, 88percent). 1H NMR 8 3.25 (m, 1 H), 3.30 (m, 1 H), 3.40 (m, 1 H), 3.83 (m, 1 H), 4.77 (br s, 1 H), 7.06 (m, 2 H), 7.37(m, 2 H).a) General procedure: A solution of (R)-4-chlorophenylglycine methyl ester hydrochloride (2.00g, 8.50mmol) in aqueous ethanol (50percent, 50mL) was added slowly over 5min to a solution of sodium borohydride (1.54g, 40.71mmol) in aqueous ethanol (50percent, 50mL) at 0°C. The suspension was stirred at room temperature for 4.5h, then heated at reflux for 3h and stirred at room temperature overnight. Water was added to dissolve the remaining solids and the reaction mixture transferred to a separating funnel and extracted with diethyl ether (3×50mL). The combined organic layers were washed with brine (100mL), dried, filtered and concentrated under reduced pressure to give the amino alcohol 9 (1.20g, 82percent) as a white solid which was used without further purificationa 1. To a stirred solution of lithium aluminium hydride (1.0 M in THF, 11.9 ml, 11.9 mmol) at0 C was added 4- (R)-fluorophenylglycine (1.0 g, 5.9 mmol) portion wise over 1 hour. The mixture was stirred at room temperature for 16 hours. Water (0.45 ml), 4 NNaOH (0.45 ml) and water (1.34 ml) was added to the mixture and the mixture was stirred for 10 minutes before being filtered. The filtrate was concentrated to give a yellow residue. Flash chromatography(CombiFlash, CH2Cl2/MeOH/NH3 = 90/10/1) gave productas a white solid (800 mg, 88%). 1H NMR 8 3.25 (m, 1 H), 3.30 (m, 1 H), 3.40 (m, 1 H), 3.83 (m, 1 H), 4.77 (br s, 1 H), 7.06 (m, 2 H), 7.37(m, 2 H).a) Preparation of (R)-2-(4-fluoro-phenyl)-1-hydroxymethyl-ethylamine To the solution of sodium borohydride (0.54 g, 14.2 mmol) in THF (10 mL) was added D-4-Fluorophenylglycine (1.0 g, 5.9 mmol). After cooling to 0 C., the solution of iodine (1.5 g, 5.9 mmol) in THF (10 mL) was added dropwisely. The mixture was stirred at reflux for 18 h. after cooling to the room temperature, methanol (7 mL) was added to stop the reaction. After removal of solvent, 20% potassium hydroxide (50 mL) was added. The mixture was stirred for 4 h and extracted with methylene chloride (3*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-10% methanol in methylene chloride in 30 min afforded (R)-2-(4-fluoro-phenyl)-1-hydroxymethyl-ethylamine (0.63 g, 69%).: Lithium aluminum hydride (348 mg, 9.16 mmol) was suspended in anhydrous THF (5 ml) under nitrogen atmosphere and cooled to 0 C. (R)-2-amino-2-(4-fluorophenyl)acetic acid (500 mg, 2.96 mmol) dissolved in THF (11 ml) was then added dropwise. After the addition was complete, the reaction mixture was refluxed overnight. After cooling the mixture to 0 C., water (0.3 ml) was added slowly, followed by sat. K2CO3aq. (0.3 ml). Addition of an excess of K2CO3 powder was followed by filtration, washing with THF and CHCl3 and evaporation of the solvents. The product (258 mg) was obtained in 57% yield after column chromatography (DCM/MeOH gradient). LRMS (ESI+) (M+H): 156.081. (R)-2-Amino-2-(4-fluorophenyl)-1-methoxy ethane. Hydrogen chloride. A solution of 2. 1-{3-[5-(1, 2, 4-Triazol-4-yl)-1H-indol-3-yl]propyl}-4-{[(R)-2-hydroxy-1-(4-fluorophenyl)ethyl]amino}piperidine. 2.0 Hydrogen Oxalate. This was prepared from 1-{3-[5-(1, 2, 4-triazol-4-yl)-1H-indol-3-yl]propyl}-4-ketopiperidine and General procedure: To a solution of 1, 2-azido alcohol 5 (1mmol) in THF (5mL) was added triphenylphosphine (393mg, 1.5mmol) and water (360mg, 20mmol). The mixture was heated at 70C for 1-2h until TLC analysis showed that the reaction was complete. Next, the mixture was concentrated under vacuum and purified by preparative TLC to afford the desired product.

Molecular Weight:155.17
XLogP3:0.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:155.074642105
Monoisotopic Mass:155.074642105
Topological Polar Surface Area:46.2
Heavy Atom Count:11
Complexity:113
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes