3,3-dimethoxypropanoic acid

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

Procedure: A solution of 1.26 g (2.96 mmol) of (S)-4-benzyloxy-2-[2-(3,4-dichloro-phenylamino)-propylamino]-butyric acid methyl ester in 30 ml CH2Cl2 was treated with a solution of 0.91 g (3.55 mmol) of 2-chloro-1-methylpyridinium iodide and 0.48 g (3.55 mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl 3,3-dimethoxy-propionate by hydrolysis with LiOH) in 20 ml of CH2Cl2. The suspension was cooled and treated at 0° C. with 1.77 ml (7.41 mmol) of tributylamine. The cooling bath was removed after 10 min and stirring was continued over night. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over Na2SO4 to yield 1.53 g (96%) of the title compound as a 71:29 mixture of the (R) and (S) diastereomers. Yellow oil, MS: 541.2 (MH+, 2Cl). The suspension was cooled The cooling bath was removed after 10 min was continued over night The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×) The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution dried over Na2SO4

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

Procedure: A solution of 1.26 g (2.96 mmol) of (S)-4-benzyloxy-2-[2-(3,4-dichloro-phenylamino)-propylamino]-butyric acid methyl ester in 30 ml CH2Cl2 was treated with a solution of 0.91 g (3.55 mmol) of 2-chloro-1-methylpyridinium iodide and 0.48 g (3.55 mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl 3,3-dimethoxy-propionate by hydrolysis with LiOH) in 20 ml of CH2Cl2. The suspension was cooled and treated at 0° C. with 1.77 ml (7.41 mmol) of tributylamine. The cooling bath was removed after 10 min and stirring was continued over night. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over Na2SO4 to yield 1.53 g (96%) of the title compound as a 71:29 mixture of the (R) and (S) diastereomers. Yellow oil, MS: 541.2 (MH+, 2Cl). The suspension was cooled The cooling bath was removed after 10 min was continued over night The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×) The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution dried over Na2SO4

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled solution (0° C.) of 2-methoxy-5-acetyloxy-aniline (5 g, 0.0276 mole), 3,3-dimethoxy-propanoic acid (5 g, 0.0373 mole) in 75 ml of methylene chloride was added DCC (5.7 g, 0.0276 mole) in 20 ml of methylene chloride. After completion of the addition, the solution was stirred for a further 4 hours. The reaction medium was concentrated to 25 ml, diluted with 200 ml of isopropyl ether, cooled to 5° C. and the resulting precipitate was isolated by filtration, giving N-(3,3-dimethoxypropanoyl)-2-methoxy-5-acetoxy-aniline 7.7 g (Yield=95%). After completion of the addition The reaction medium was concentrated to 25 ml diluted with 200 ml of isopropyl ether the resulting precipitate was isolated by filtration

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

Procedure: 50 g (0.33 mol.) of Methyl 3,3-dimethoxy-propanoate in 200 ml of 2N NaOH solution in water were refluxed 2 hours. After cooling the solution was acidified with hydrochloric acid then extracted two times with 200 ml of CH2Cl2. The extracts were dried on sodium sulfate and evaporated to leave 35 g (Yield=78%) of 3,3-dimethoxy-propanoic acid as an oil. After cooling the solution then extracted two times with 200 ml of CH2Cl2 The extracts were dried on sodium sulfate evaporated

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

Procedure: 50 g (0.33 mol.) of Methyl 3,3-dimethoxy-propanoate in 200 ml of 2N NaOH solution in water were refluxed 2 hours. After cooling the solution was acidified with hydrochloric acid then extracted two times with 200 ml of CH2Cl2. The extracts were dried on sodium sulfate and evaporated to leave 35 g (Yield=78%) of 3,3-dimethoxy-propanoic acid as an oil. After cooling the solution then extracted two times with 200 ml of CH2Cl2 The extracts were dried on sodium sulfate evaporated

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

Procedure: A solution of 1.25 g (3.20 mmol) of 4-[(R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propylamino]-butyric acid tert-butyl ester (22% ee) in 25 ml CH2Cl2 was treated with a solution of 1.00 g (3.80 mmol) of 2-chloro-1-methylpyridinium iodide and 0.51 g (3.80 mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl 3,3-dimethoxy-propionate by hydrolysis with LiOH) in 5 ml of CH2Cl2. The suspension was cooled and treated at 0° C. with 1.89 ml (7.90 mmol) of tributylamine. The reaction was naturally warmed to RT over night. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over Na2SO4 to yield 1.68 g (quantitative) of the title compound as a 61:39 mixture of the (R) and (S) diastereomers as light brown oil. MS: 511.22 (MH+, Cl). The suspension was cooled The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×) The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution dried over Na2SO4

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

Procedure: A solution of 1.26 g (2.96 mmol) of (S)-4-benzyloxy-2-[2-(3,4-dichloro-phenylamino)-propylamino]-butyric acid methyl ester in 30 ml CH2Cl2 was treated with a solution of 0.91 g (3.55 mmol) of 2-chloro-1-methylpyridinium iodide and 0.48 g (3.55 mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl 3,3-dimethoxy-propionate by hydrolysis with LiOH) in 20 ml of CH2Cl2. The suspension was cooled and treated at 0° C. with 1.77 ml (7.41 mmol) of tributylamine. The cooling bath was removed after 10 min and stirring was continued over night. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over Na2SO4 to yield 1.53 g (96%) of the title compound as a 71:29 mixture of the (R) and (S) diastereomers. Yellow oil, MS: 541.2 (MH+, 2Cl). The suspension was cooled The cooling bath was removed after 10 min was continued over night The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×) The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution dried over Na2SO4

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled solution (0° C.) of 2-methoxy-5-acetyloxy-aniline (5 g, 0.0276 mole), 3,3-dimethoxy-propanoic acid (5 g, 0.0373 mole) in 75 ml of methylene chloride was added DCC (5.7 g, 0.0276 mole) in 20 ml of methylene chloride. After completion of the addition, the solution was stirred for a further 4 hours. The reaction medium was concentrated to 25 ml, diluted with 200 ml of isopropyl ether, cooled to 5° C. and the resulting precipitate was isolated by filtration, giving N-(3,3-dimethoxypropanoyl)-2-methoxy-5-acetoxy-aniline 7.7 g (Yield=95%). After completion of the addition The reaction medium was concentrated to 25 ml diluted with 200 ml of isopropyl ether the resulting precipitate was isolated by filtration

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

Procedure: 50 g (0.33 mol.) of Methyl 3,3-dimethoxy-propanoate in 200 ml of 2N NaOH solution in water were refluxed 2 hours. After cooling the solution was acidified with hydrochloric acid then extracted two times with 200 ml of CH2Cl2. The extracts were dried on sodium sulfate and evaporated to leave 35 g (Yield=78%) of 3,3-dimethoxy-propanoic acid as an oil. After cooling the solution then extracted two times with 200 ml of CH2Cl2 The extracts were dried on sodium sulfate evaporated