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N-Boc-3-pyrrolidone (0.010 mmol) was submitted to Procedure 9 to yield the desired N-Boc-S-hydroxy-pyrrolidine-S-carboxylic acid.N-Boc-l-amino-but-3-ene3-Buten-l -amine (4.93 g, 0.069 mol) was submitted to Procedure 7 for Boc protection to yield a crude, which was purified by flash chromatography (silica gel/hexanes: ethyl acetate 0-30%) to yield N-Boc-l-amino-but-3-ene (6.47 g, 0.038 mol, 55.1 % yield).; Step No. 3. Boc protection: To a stirring solution of solid from step No.2 in2 M NaOH (20 mL) and i-PrOH (20 mL) at 0C was added BoC2O (6.6 g, 3 mmol) in small portions, and the reaction mixture was allowed to warm to room temperature over4 h. i-PrOH was then evaporated, and H2O (50 mL) was added, and the aqueous phase was separated and extracted with Et2O (2 x 30 ml). The aqueous layer was acidified to pH 3 by addition of dilute H3PO4 and was extracted with EtOAc (2 x 60 ml). The combined organic layers were washed with H2O (2 x 30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to yield the desired N-Boc-alpha-hydroxy carboxylic acids in 56-72% yield.
With sodium hydroxide; In isopropyl alcohol; at 0 - 20℃;
N-Boc-3-pyrrolidone (0.010 mmol) was submitted to Procedure 9 to yield the desired N-Boc-3 -hydroxy-pyrrolidine-3 -carboxylic acid.
With sodium hydroxide; In water; isopropyl alcohol; at 0 - 20℃; for 4h;
Step No. 3. Boc protection: To a stirring solution of solid from step No.2 in2 M NaOH (20 mL) and i-PrOH (20 mL) at 00C was added BoC2O (6.6 g, 3 mmol) in small portions, and the reaction mixture was allowed to warm to room temperature over 4 h. i-PrOH was then evaporated, and H2O (50 mL) was added, and the aqueous phase was separated and extracted with Et2O (2 x 30 ml). The aqueous layer was acidified to pH 3 by addition of dilute H3PO4 and was extracted with EtOAc (2 x 60 ml). The combined organic layers were washed with H2O (2 x 30 mL) and brine (30 mL), dried <n="46"/>over Na2SO4, filtered and concentrated to yield the desired N-Boc-alpha-hydroxy carboxylic acids in 56-72% yield. Example 34 6'-(2-Hydroxy-ethyl)-l-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomicinN-Boc-S-hydroxypyrrolidine-S-carboxylic acidN-Boc-3-pyrrolidone (0.010 mmol) was submitted to Procedure 15 to yield the desired N-Boc-S-hydroxy-pyrrolidine-S-carboxylic acid.
N-Boc-3-pyrrolidone (0.010 mmol) was submitted to Procedure 9 to yield the desired N-Boc-S-hydroxy-pyrrolidine-S-carboxylic acid..; Step No. 3. Boc protection: To a stirring solution of solid from step No.2 in2 M NaOH (20 mL) and i-PrOH (20 mL) at 0C was added BoC2O (6.6 g, 3 mmol) in small portions, and the reaction mixture was allowed to warm to room temperature over4 h. i-PrOH was then evaporated, and H2O (50 mL) was added, and the aqueous phase was separated and extracted with Et2O (2 x 30 ml). The aqueous layer was acidified to pH 3 by addition of dilute H3PO4 and was extracted with EtOAc (2 x 60 ml). The combined organic layers were washed with H2O (2 x 30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to yield the desired N-Boc-alpha-hydroxy carboxylic acids in 56-72% yield.
General Procedure for Synthesis of q-hydroxy carboxylic acids. Step No. 1. O-(Trimethylsilyl) cyanohydrines: A 50-mL flask equipped with a magnetic stirring bar and drying tube was charged with the ketone or aldehyde (0.010 mmol), followed by THF (50 mL), trimethylsilyl cyanide (1.39 g, 14 mmol), and zinc iodide (0.090 g, 0.28 mmol), and the reaction mixture was stirred at room temperature for 24 hr. Solvent evaporation gave a residue, which was dissolved in EtOAc (60 mL), washed with 5% aq. NaHC03 (2 x 30 mL), H20 (30 mL), and brine (30 mL), dried over Na2S04, filtered and concentrated to dryness to yield a crude, which was carried through to the next step without further purification. Step No. 2. Acid hydrolysis to g-hydroxy carboxylic acid: AcOH (25 ml) and cone. HC1 (25 ml) were added to the unpurified material from step No.1 and the reaction mixture was refluxed for 2-3 hr. The reaction mixture was then concentrated to dryness to give a white solid, which was carried through to the next step without further purification.Step No. 3. Boc protection: To a stirring solution of solid from step No.2 in 2 M NaOH (20 mL) and i-PrOH (20 mL) at 0C was added Boc20 (6.6 g, 3 mmol) in small portions, and the reaction mixture was allowed to warm to room temperature over 4 h. i-PrOH was then evaporated, and H20 (50 mL) was added, and the aqueous phase was separated and extracted with Et20 (2 x 30 ml). The aqueous layer was acidified to pH 3 by addition of dilute H3P04 and was extracted with EtOAc (2 x 60 ml). The combined organic layers were washed with H20 (2 x 30 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated to yield the desired N-Boc-a-hydroxy carboxylic acids in 56-72% yield.
N-Boc-3-hydroxypyrrolidine-3-carboxylic acidN-Boc-3-pyrrolidone (0.010 mmol) was submitted to Procedure 15 to yield the desired N-Boc-S-hydroxy-pyrrolidine-S-carboxylic acid; Procedure 15: General Procedure for Synthesis of alpha-hydroxy carboxylic acidsStep No. 1. O-(Trimethylsilyl) cvanohydrines: A 50-mL flask equipped with a magnetic stirring bar and drying tube was charged with the ketone or aldehyde (0.010 mmol), followed by THF (50 mL), trimethylsilyl cyanide (1.39 g, 14 mmol), and zinc iodide (0.090 g, 0.28 mmol), and the reaction mixture was stirred at room temperature for 24 hr. Solvent evaporation gave a residue, which was dissolved in EtOAc (60 niL), washed with 5% aq. NaHCO3 (2 x 30 mL), H2O (30 mL), and brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness to yield a crude, which was carried through to the next step without further purification.Step No. 2. Acid hydrolysis to alpha-hydroxy carboxylic acid: AcOH (25 ml) and cone. HCl (25 ml) were added to the unpurified material from step No.1 and the reaction mixture was refluxed for 2-3 hr. The reaction mixture was then concentrated to dryness to give a white solid, which was carried through to the next step without further purification.Step No. 3. Boc protection: To a stirring solution of solid from step No.2 in 2 M NaOH (20 mL) and i-PrOH (20 mL) at 00C was added BoC2O (6.6 g, 3 mmol) in small portions, and the reaction mixture was allowed to warm to room temperature over 4 h. i-PrOH was then evaporated, and H2O (50 mL) was added, and the aqueous phase was separated and extracted with Et2O (2 x 30 ml). The aqueous layer was acidified to pH 3 by addition of dilute H3PO4 and was extracted with EtOAc (2 x 60 ml). The combined organic layers were washed with H2O (2 x 30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to yield the desired N-Boc-alpha-hydroxy carboxylic acids in 56-72% yield. Aldehydes and ketones used: N-Boc-3-Pyrrolidonone, N-Boc-3- azetidinone, N-Boc-4-piperidone and N-Boc-3-azetidincarboxaldehyde.
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