(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(3-chlorophenyl)acetaldehyde

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

Procedure: To a stirred solution of (R)-(3-chloro-phenyl)-(tert-butyl-dimethyl-silanoxy)-acetic acid methyl ester (4.0 g) in anhydrous ether (10 ml) and maintained at <-65° was added dropwise a 1.5M solution of di-isobututylaluminium hydride in toluene (10 ml). When addition was complete the solution was stirred at -65° for a further hour, then quenched with methanol (10 ml). The mixture was allowed to attain room temperature when silica (20 g) was added. Solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a colourless liquid (3.1 g). When addition quenched with methanol (10 ml) to attain room temperature was added Solvent was removed under reduced pressure the residue was purified by flash chromatography eluting with cyclohexane:ethyl acetate (9:1)

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

Procedure: Following a procedure similar to that described in Preparation 29, but using 5.2 g of (R)-α-t-butyl-dimethylsilyloxy-α-(3-chlorophenyl)acetaldehyde (prepared as described in Preparation 49), 4.24 g of methyl 4-[2(R)-amino-1-propoxy]phenylacetate (prepared as described in Preparation 27), 50 ml of absolute methanol and 3.4 g of sodium cyanoborohydride, the title compound was obtained having an Rf=0.20 (thin layer chromatography over silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent). that described in Preparation 29

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 26 g of methyl (R)-α-t-butyldimethylsilyloxy-3-chlorophenylacetate (prepared as described in Preparation 48) in a mixture of 1000 ml of anhydrous hexane and 500 ml of dry toluene was cooled to -60° C., and then 124 ml of a 1M solution of diisobutylaluminum hydride in hexane were added dropwise to the cooled solution. The resulting mixture was stirred at the same temperature for 3 hours, after which 10 ml of water were added to it, and the temperature of the mixture was gradually allowed to rise to room temperature. The reaction mixture was then mixed with water and ethyl acetate, after which it was stirred for 30 minutes. Insoluble materials were filtered off using a Celite (trade mark) filter aid, and the ethyl acetate layer was separated from the filtrate and dried over anhydrous sodium sulfate. The ethyl acetate solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound having an Rf=0.36 (thin layer chromatography over silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the developing solvent). to rise to room temperature after which it was stirred for 30 minutes Insoluble materials were filtered off filter aid the ethyl acetate layer was separated from the filtrate dried over anhydrous sodium sulfate The ethyl acetate solvent was removed by distillation under reduced pressure the residue was purified by column chromatography through silica gel by volume mixture of ethyl acetate and hexane as the eluent

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

Procedure: Following a procedure similar to that described in Preparation 29, but using 5.2 g of (R)-α-t-butyldimethylsilyloxy-α-(3-chlorophenyl)acetaldehyde (prepared as described in Preparation 49), 4.24 g of methyl 4-[2(R)-amino-1-propoxy]phenylacetate (prepared as described in Preparation 27), 50 ml of absolute methanol and 3.4 g of sodium cyanoborohydride, the title compound was obtained having an Rf=0.20 (thin layer chromatography over silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent). [α]D23 -34.7° (c=1.024, chloroform). that described in Preparation 29

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 26 g of methyl (R)-α-t-butyldimethylsilyloxy-3-chlorophenylacetate (prepared as described in Preparation 48) in a mixture of 1000 ml of anhydrous hexane and 500 ml of dry toluene was cooled to -60° C., and then 124 ml of a 1M solution of diisobutylaluminum hydride in hexane were added dropwise to the cooled solution. The resulting mixture was stirred at the same temperature for 3 hours, after which 10 ml of water were added to it, and the temperature of the mixture was gradually allowed to rise to room temperature. The reaction mixture was then mixed with water and ethyl acetate, after which it was stirred for 30 minutes. Insoluble materials were filtered off using a Celite (trade mark) filter aid, and the ethyl acetate layer was separated from the filtrate and dried over anhydrous sodium sulfate. The ethyl acetate solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound having an Rf=0.36 (thin layer chromatography over silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the developing solvent). to rise to room temperature after which it was stirred for 30 minutes Insoluble materials were filtered off filter aid the ethyl acetate layer was separated from the filtrate dried over anhydrous sodium sulfate The ethyl acetate solvent was removed by distillation under reduced pressure the residue was purified by column chromatography through silica gel by volume mixture of ethyl acetate and hexane as the eluent

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 26 g of methyl (R)-α-t-butyldimethylsilyloxy-3-chlorophenylacetate [prepared as described in Step (d), above] in a mixture of 1000 ml of anhydrous hexane and 500 ml of dry toluene was cooled to -60° C., and then 124 ml of a 1M solution of diisobutylaluminum hydride in hexane were added dropwise to the cooled solution. The resulting mixture was stirred at the same temperature for 3 hours, after which 10 ml of water were added to it, and the temperature of the mixture was gradually allowed to rise to room temperature. The reaction mixture was then mixed with water and ethyl acetate, after which it was stirred for 30 minutes. Insoluble materials were filtered off using a Celite (trade mark) filter aid, and the ethyl acetate layer was separated from the filtrate and dried over anhydrous sodium sulfate. The ethyl acetate solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the eluent, to give 5.41 g of the title compound having an Rf=0.36 (thin layer chromatography on silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the developing solvent). to rise to room temperature after which it was stirred for 30 minutes Insoluble materials were filtered off filter aid the ethyl acetate layer was separated from the filtrate dried over anhydrous sodium sulfate The ethyl acetate solvent was removed by distillation under reduced pressure the residue was purified by column chromatography through silica gel by volume mixture of ethyl acetate and hexane as the eluent

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

Procedure: A mixture of 36.5 g of 5-{4-[2(R)-aminopropoxy]benzyl}thiazolidine-2,4-dione trifluoroacetate [prepared as described in Preparation 2], 98.4 g of (R)-α-(t-butyldimethylsilyloxy)-α-(3-chlorophenyl)acetaldehyde [prepared as described in Preparation 12] and 400 ml of absolute methanol was stirred at room temperature for 2.5 hours, after which the mixture was cooled using a salted ice-bath. 29.0 g of sodium cyanoborohydride were then added to the mixture in small portions, and the mixture was allowed to stand overnight at room temperature. At the end of this time, the methanol was distilled off under reduced pressure, the residue was mixed with water and ethyl acetate, and the ethyl acetate layer was separated from the mixture. The ethyl acetate layer was then washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 46.5 g of the title compound. after which the mixture was cooled to stand overnight at room temperature At the end of this time, the methanol was distilled off under reduced pressure the residue was mixed with water and ethyl acetate the ethyl acetate layer was separated from the mixture The ethyl acetate layer was then washed with a saturated aqueous solution of sodium chloride after which it was dried over anhydrous sodium sulfate The solvent was then distilled off under reduced pressure The residue was purified by column chromatography through silica gel by volume mixture of ethyl acetate and hexane as the eluent

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

Procedure: To a stirred solution of (R)-(3-chloro-phenyl)-(tert-butyl-dimethyl-silanoxy)-acetic acid methyl ester (4.0 g) in anhydrous ether (10 ml) and maintained at <-65° was added dropwise a 1.5M solution of di-isobututylaluminium hydride in toluene (10 ml). When addition was complete the solution was stirred at -65° for a further hour, then quenched with methanol (10 ml). The mixture was allowed to attain room temperature when silica (20 g) was added. Solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a colourless liquid (3.1 g). When addition quenched with methanol (10 ml) to attain room temperature was added Solvent was removed under reduced pressure the residue was purified by flash chromatography eluting with cyclohexane:ethyl acetate (9:1)