methyl 3-methoxypropanoate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flame-dried flask was charged with 5 ml (8.0 mmol) n-butyllithium (1.6 M solution in hexanes) in dry THF (25 ml) under inert gas atmosphere and cooled to −78° C. Next, 0.368 ml (7 mmol) acetonitrile were slowly added, and the resulting mixture was stirred for 1 h at −70° C. Then, 0.585 ml (5.0 mmol) methyl 3-methoxypropanoate were slowly added maintaining the temperature below −66° C. The reaction mixture was stirred for 2 h at −45° C. and then quenched by addition of hydrochloric acid (2 M, 16 ml) keeping the temperature below −35° C. The resulting clear solution was allowed to warm to room temperature and then concentrated under reduced pressure, and the residue was dried under high vacuum. The crude product thus obtained (1.51 g) was used in the next step without further purification. maintaining the temperature below −66° C The reaction mixture was stirred for 2 h at −45° C. quenched by addition of hydrochloric acid (2 M, 16 ml) the temperature below −35° C to warm to room temperature concentrated under reduced pressure the residue was dried under high vacuum

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

Procedure: 3-Methoxy-propionic acid methyl ester (9.95 g, 84.2 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (89 mL, 88.9 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0 g, 42.2 mmol) was then added neat and the reaction mixture brought to reflux for 7 days. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude product was dissolved in ethyl acetate and diluted with hexanes to give a precipitate which was collected by filtration to give 8-cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (3.11 g, 24.1%). 1H NMR 6 (400 MHz, CDCl3) 8.46 (s, 1H), 7.49 (t, J=1.7 Hz, 1H), 5.81 (m, 1H), 4.28 (d, J=1.7 Hz, 1H), 3.37 (s, 3H), 2.47 (s, 3H), 2.18 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H). was slowly added to reflux for 7 days the layers separated the organic layer dried over MgSO4 the solvent evaporated to give a crude oil to give a precipitate which was collected by filtration

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

Procedure: 3-Methoxy-propionic acid methyl ester (9.95 g, 84.2 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (89 mL, 88.9 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0 g, 42.2 mmol) was then added neat and the reaction mixture brought to reflux for 7 days. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude product was dissolved in ethyl acetate and diluted with hexanes to give a precipitate which was collected by filtration to give 8-cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (3.11 g, 24.1%). 1H NMR 6 (400 MHz, CDCl3) 8.46 (s, 1H), 7.49 (t, J=1.7 Hz, 1H), 5.81 (m, 1H), 4.28 (d, J=1.7 Hz, 1H), 3.37 (s, 3H), 2.47 (s, 3H), 2.18 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H). was slowly added to reflux for 7 days the layers separated the organic layer dried over MgSO4 the solvent evaporated to give a crude oil to give a precipitate which was collected by filtration

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

Procedure: 3-Methoxy-propionic acid methyl ester (9.95 g, 84.2 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (89 mL, 88.9 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0 g, 42.2 mmol) was then added neat and the reaction mixture brought to reflux for 7 days. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude product was dissolved in ethyl acetate and diluted with hexanes to give a precipitate which was collected by filtration to give 8-cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (3.11 g, 24.1%). 1H NMR δ (400 MHz, CDCl3) 8.46 (s, 1H), 7.49 (t, J=1.7 Hz, 1H), 5.81 (m, 1H), 4.28 (d, J=1.7 Hz, 1H), 3.37 (s, 3H), 2.47 (s, 3H), 2.18 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H). was slowly added to reflux for 7 days the layers separated the organic layer dried over MgSO4 the solvent evaporated to give a crude oil to give a precipitate which was collected by filtration

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flame-dried flask was charged with 5 ml (8.0 mmol) n-butyllithium (1.6 M solution in hexanes) in dry THF (25 ml) under inert gas atmosphere and cooled to −78° C. Next, 0.368 ml (7 mmol) acetonitrile were slowly added, and the resulting mixture was stirred for 1 h at −70° C. Then, 0.585 ml (5.0 mmol) methyl 3-methoxypropanoate were slowly added maintaining the temperature below −66° C. The reaction mixture was stirred for 2 h at −45° C. and then quenched by addition of hydrochloric acid (2 M, 16 ml) keeping the temperature below −35° C. The resulting clear solution was allowed to warm to room temperature and then concentrated under reduced pressure, and the residue was dried under high vacuum. The crude product thus obtained (1.51 g) was used in the next step without further purification. maintaining the temperature below −66° C The reaction mixture was stirred for 2 h at −45° C. quenched by addition of hydrochloric acid (2 M, 16 ml) the temperature below −35° C to warm to room temperature concentrated under reduced pressure the residue was dried under high vacuum

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flame-dried flask was charged with 5 ml (8.0 mmol) n-butyllithium (1.6 M solution in hexanes) in dry THF (25 ml) under inert gas atmosphere and cooled to −78° C. Next, 0.368 ml (7 mmol) acetonitrile were slowly added, and the resulting mixture was stirred for 1 h at −70° C. Then, 0.585 ml (5.0 mmol) methyl 3-methoxypropanoate were slowly added maintaining the temperature below −66° C. The reaction mixture was stirred for 2 h at −45° C. and then quenched by addition of hydrochloric acid (2 M, 16 ml) keeping the temperature below −35° C. The resulting clear solution was allowed to warm to room temperature and then concentrated under reduced pressure, and the residue was dried under high vacuum. The crude product thus obtained (1.51 g) was used in the next step without further purification. maintaining the temperature below −66° C The reaction mixture was stirred for 2 h at −45° C. quenched by addition of hydrochloric acid (2 M, 16 ml) the temperature below −35° C to warm to room temperature concentrated under reduced pressure the residue was dried under high vacuum

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

Procedure: 3-Methoxy-propionic acid methyl ester (9.95 g, 84.2 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (89 mL, 88.9 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0 g, 42.2 mmol) was then added neat and the reaction mixture brought to reflux for 7 days. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude product was dissolved in ethyl acetate and diluted with hexanes to give a precipitate which was collected by filtration to give 8-cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (3.11 g, 24.1%). 1H NMR 6 (400 MHz, CDCl3) 8.46 (s, 1H), 7.49 (t, J=1.7 Hz, 1H), 5.81 (m, 1H), 4.28 (d, J=1.7 Hz, 1H), 3.37 (s, 3H), 2.47 (s, 3H), 2.18 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H). was slowly added to reflux for 7 days the layers separated the organic layer dried over MgSO4 the solvent evaporated to give a crude oil to give a precipitate which was collected by filtration

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

Procedure: A solution of 2.6 g (22.0 mmol) of methyl 3-methoxy-propionate in 5 ml of tetrahydrofuran was added to a solution of 666 mg of sodium hydride in 15 ml of tetrahydrofuran solution with ice cooling, subsequently to the resulting solution was added a solution of 3 g (1.1 mmol) of 3,5-dimethoxy-4-(β-methoxyethoxy)methoxybenzaldehyde in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature for 17 hours. The mixture was extracted with 60 ml of ethyl acetate after adding ice to the solution. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily product thus obtained was dissolved in 20 ml of tetrahydrofuran. An aqueous potassium hydroxide solution (740 mg/5 ml) was added to the solution. The mixture was stirred at room temperature for 21 hours. The solution was evaporated under reduced pressure. A 40 ml of water was added to the residue, and the aqueous solution was washed with 30 ml of ethyl acetate. The aqueous layer was neutralized with acetic acid and extracted with 60 ml of methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2.5 g (yield 63.2%) of a desired α-methoxymethyl-3,5-dimethoxy-4-(β-methoxyethoxy)-methoxycinnamic acid. The mixture was extracted with 60 ml of ethyl acetate after adding ice to the solution The organic layer was washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure The oily product thus obtained The mixture was stirred at room temperature for 21 hours The solution was evaporated under reduced pressure A 40 ml of water was added to the residue the aqueous solution was washed with 30 ml of ethyl acetate extracted with 60 ml of methylene chloride The organic layer was dried over anhydrous magnesium sulfate evaporated under reduced pressure

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

Procedure: A 50 cm long, 5 cm diameter water-jacketted reactor (Reactor C) was charged with 1 liter of Dowex MSA 1 strong base resin. The resin was treated in sequence with 2000 ml of ethanol, 2000 ml of water, 3800 ml of 4 weight percent aqueous sodium hydroxide, and 5000 ml of methanol-ethanol mixture. This reactor was used to react mixtures containing ethyl acrylate and both methanol and ethanol to produce mixtures of ethyl 3-methoxypropanoate, methyl 3-ethoxypropanoate, ethyl 3-ethoxypropanoate and methyl 3-methoxypropanoate. In each run about 7.5 liters of a feed solution containing the components identified in Table IV was used. There was no problem of ethyl acrylate breakthrough at the end of each run. The mixture was recovered by distillation to remove the alcohols. was charged with 1 liter of Dowex MSA 1 strong base resin This reactor was used to react mixtures

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

Procedure: 3-Methoxy-propionic acid methyl ester (9.95 g, 84.2 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (89 mL, 88.9 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0 g, 42.2 mmol) was then added neat and the reaction mixture brought to reflux for 7 days. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude product was dissolved in ethyl acetate and diluted with hexanes to give a precipitate which was collected by filtration to give 8-cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (3.11 g, 24.1%). 1H NMR δ (400 MHz, CDCl3) 8.46 (s, 1H), 7.49 (t, J=1.7 Hz, 1H), 5.81 (m, 1H), 4.28 (d, J=1.7 Hz, 1H), 3.37 (s, 3H), 2.47 (s, 3H), 2.18 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H). was slowly added to reflux for 7 days the layers separated the organic layer dried over MgSO4 the solvent evaporated to give a crude oil to give a precipitate which was collected by filtration

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

Procedure: 3-Methoxy-propionic acid methyl ester (9.95 g, 84.2 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (89 mL, 88.9 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (10.0 g, 42.2 mmol) was then added neat and the reaction mixture brought to reflux for 7 days. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude product was dissolved in ethyl acetate and diluted with hexanes to give a precipitate which was collected by filtration to give 8-cyclopentyl-6-methoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid (3.11 g, 24.1%). 1H NMR δ (400 MHz, CDCl3) 8.46 (s, 1H), 7.49 (t, J=1.7 Hz, 1H), 5.81 (m, 1H), 4.28 (d, J=1.7 Hz, 1H), 3.37 (s, 3H), 2.47 (s, 3H), 2.18 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H). was slowly added to reflux for 7 days the layers separated the organic layer dried over MgSO4 the solvent evaporated to give a crude oil to give a precipitate which was collected by filtration

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flame-dried flask was charged with 5 ml (8.0 mmol) n-butyllithium (1.6 M solution in hexanes) in dry THF (25 ml) under inert gas atmosphere and cooled to −78° C. Next, 0.368 ml (7 mmol) acetonitrile were slowly added, and the resulting mixture was stirred for 1 h at −70° C. Then, 0.585 ml (5.0 mmol) methyl 3-methoxypropanoate were slowly added maintaining the temperature below −66° C. The reaction mixture was stirred for 2 h at −45° C. and then quenched by addition of hydrochloric acid (2 M, 16 ml) keeping the temperature below −35° C. The resulting clear solution was allowed to warm to room temperature and then concentrated under reduced pressure, and the residue was dried under high vacuum. The crude product thus obtained (1.51 g) was used in the next step without further purification. maintaining the temperature below −66° C The reaction mixture was stirred for 2 h at −45° C. quenched by addition of hydrochloric acid (2 M, 16 ml) the temperature below −35° C to warm to room temperature concentrated under reduced pressure the residue was dried under high vacuum