ethyl 4-ethoxybutanoate

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

Procedure: To a cooled (−78° C.) solution of 4-ethoxy-butyric acid ethyl ester (9.85 g, 61.47 mmol) in THF (25 ml) was added lithium bis(trimethylsilyl)amide (77.0 ml, 76.85 mmol, 1 M solution in THF). The reaction mixture was stirred for 10 minutes to form the anion. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethylacetate (150 ml total) and the organic layers were combined and concentrated to give a yellow oil. Chromatographic purification on silica gel (chloroform/ethyl acetate gradient) gave 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.22 g, 9.65 mmol). MS (APCl+)334 (M+1, 100); 1H NMR δ(400 MHz, DMSO-d6) 8.54 (s, 1H), 7.47-7.46 (m, 1H), 5.99-5.90 (m, 1H), 3.69 (t, J=6.25 Hz, 2H), 3.49 (q, J=7.03 Hz, 2H), 2.84 (t, J=6.25 Hz, 2H), 2.59 (s, 3H), 2.34-2.29 (m, 2H), 2.08-2.02 (m, 2H), 1.88-1.83 (m, 2H), 1.69-1.65 (m, 3H), 1.17 (t, J=7.04 Hz, 3H). to form the anion stirred overnight The reaction mixture was quenched with 10% aqueous HCl (100 ml) The aqueous layer was extracted with ethylacetate (150 ml total) concentrated to give a yellow oil Chromatographic purification on silica gel (chloroform/ethyl acetate gradient)

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

Procedure: To a cooled (−78° C.) solution of 4-ethoxy-butyric acid ethyl ester (9.85 g, 61.47 mmol) in THF (25 ml) was added lithium bis(trimethylsilyl)amide (77.0 ml, 76.85 mmol, 1 M solution in THF). The reaction mixture was stirred for 10 minutes to form the anion. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethylacetate (150 ml total) and the organic layers were combined and concentrated to give a yellow oil. Chromatographic purification on silica gel (chloroform/ethyl acetate gradient) gave 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.22 g, 9.65 mmol). MS (APCl+)334 (M+1, 100); 1H NMR δ(400 MHz, DMSO-d6) 8.54 (s, 1H), 7.47-7.46 (m, 1H), 5.99-5.90 (m, 1H), 3.69 (t, J=6.25 Hz, 2H), 3.49 (q, J=7.03 Hz, 2H), 2.84 (t, J=6.25 Hz, 2H), 2.59 (s, 3H), 2.34-2.29 (m, 2H), 2.08-2.02 (m, 2H), 1.88-1.83 (m, 2H), 1.69-1.65 (m, 3H), 1.17 (t, J=7.04 Hz, 3H). to form the anion stirred overnight The reaction mixture was quenched with 10% aqueous HCl (100 ml) The aqueous layer was extracted with ethylacetate (150 ml total) concentrated to give a yellow oil Chromatographic purification on silica gel (chloroform/ethyl acetate gradient)

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

Procedure: To an ice cold stirred solution of ethyl 4-ethoxybutanoate (30) (˜1 g) in 10 mL of tetrahydrofuran (THF) was added aqueous NaOH solution (0.62 g in 7 ml of H2O) and stirred at room temperature for 12 h, while monitoring the reaction by TLC. Most of the solvent was evaporated under reduced pressure and the residue was diluted with water (10 mL). The aqueous layer was acidified with 1N HCl solution (PH˜2) and then extracted with ethyl acetate (15 mL×3). The combined organic extracts was dried over anhydrous Na2SO4 and concentrated under vacuum to yield 0.6 g (73.14) of 4-ethoxybutanoic acid as light yellow oil. 1HNMR (400 MHz, CDCl3): δ 1.20 (t, J=9.2 Hz, 3H); 1.87-1.95 (m, 2H); 2.47 (t, J=10 Hz; 2H); 3.48 (q, J=9.2 Hz, 4H). the reaction by TLC Most of the solvent was evaporated under reduced pressure the residue was diluted with water (10 mL) extracted with ethyl acetate (15 mL×3) The combined organic extracts was dried over anhydrous Na2SO4 concentrated under vacuum

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sulfuric acid 0.25 mL (0.0045 mmol, 0.035 eq) was added to an ice cooled solution of γ-butyrolactone (28) (11.2 g, 0.13009 mmol, 1.0 eq), triethyl orthoformate (29) (41.1 mL, 0.2497 mmol., 1.92 eq) in 100 mL of ethanol. The mixture was heated at 50° C. for 12 h while monitoring the reaction by TLC. The reaction mixture was cooled to room temperature and most of the solvent was evaporated under reduced pressure. The concentrated reaction mixture was quenched with cold saturated NaHCO3 solution and extracted with ethyl acetate twice. The combined organic extracts was dried over anhydrous Na2SO4 and concentrated under vacuum to yielded 20 g (95%) of ethyl 4-ethoxybutanoate (30) as light yellow oil. 1HNMR (400 MHz, CDCl3): δ 1.16-1.28 (m, 6H); 1.87-1.91 (m, 2H); 2.39 (t, J=9.6 Hz; 2H); 3.42-3.50 (m, 2H); 3.57-3.64 (m, 2H); 4.13 (q, J=6 Hz, 2H). the reaction by TLC The reaction mixture was cooled to room temperature and most of the solvent was evaporated under reduced pressure The concentrated reaction mixture was quenched with cold saturated NaHCO3 solution extracted with ethyl acetate twice The combined organic extracts was dried over anhydrous Na2SO4 concentrated under vacuum

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sulfuric acid 0.25 mL (0.0045 mmol, 0.035 eq) was added to an ice cooled solution of γ-butyrolactone (28) (11.2 g, 0.13009 mmol, 1.0 eq), triethyl orthoformate (29) (41.1 mL, 0.2497 mmol., 1.92 eq) in 100 mL of ethanol. The mixture was heated at 50° C. for 12 h while monitoring the reaction by TLC. The reaction mixture was cooled to room temperature and most of the solvent was evaporated under reduced pressure. The concentrated reaction mixture was quenched with cold saturated NaHCO3 solution and extracted with ethyl acetate twice. The combined organic extracts was dried over anhydrous Na2SO4 and concentrated under vacuum to yielded 20 g (95%) of ethyl 4-ethoxybutanoate (30) as light yellow oil. 1HNMR (400 MHz, CDCl3): δ 1.16-1.28 (m, 6H); 1.87-1.91 (m, 2H); 2.39 (t, J=9.6 Hz; 2H); 3.42-3.50 (m, 2H); 3.57-3.64 (m, 2H); 4.13 (q, J=6 Hz, 2H). the reaction by TLC The reaction mixture was cooled to room temperature and most of the solvent was evaporated under reduced pressure The concentrated reaction mixture was quenched with cold saturated NaHCO3 solution extracted with ethyl acetate twice The combined organic extracts was dried over anhydrous Na2SO4 concentrated under vacuum

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

Procedure: To a cooled (−78° C.) solution of 4-ethoxy-butyric acid ethyl ester (9.85 g, 61.47 mmol) in THF (25 ml) was added lithium bis(trimethylsilyl)amide (77.0 ml, 76.85 mmol, 1 M solution in THF). The reaction mixture was stirred for 10 minutes to form the anion. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethylacetate (150 ml total) and the organic layers were combined and concentrated to give a yellow oil. Chromatographic purification on silica gel (chloroform/ethyl acetate gradient) gave 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.22 g, 9.65 mmol). MS (APCI+) 334 (M+1, 100); 1H NMR δ (400 MHz, DMSO-d6) 8.54 (s, 1H), 7.47-7.46 (m, 1H), 5.99-5.90 (m, 1H), 3.69 (t, J=6.25 Hz, 2H), 3.49 (q, J=7.03 Hz, 2H), 2.84 (t, J=6.25 Hz, 2H), 2.59 (s, 3H), 2.34-2.29 (m, 2H), 2.08-2.02 (m, 2H), 1.88-1.83 (m, 2H), 1.69-1.65 (m, 3H), 1.17 (t, J=7.04 Hz, 3H). to form the anion stirred overnight The reaction mixture was quenched with 10% aqueous HCl (100 ml) The aqueous layer was extracted with ethylacetate (150 ml total) concentrated to give a yellow oil Chromatographic purification on silica gel (chloroform/ethyl acetate gradient)

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

Procedure: To a cooled (−78° C.) solution of 4-ethoxy-butyric acid ethyl ester (9.85 g, 61.47 mmol) in THF (25 ml) was added lithium bis(trimethylsilyl)amide (77.0 ml, 76.85 mmol, 1 M solution in THF). The reaction mixture was stirred for 10 minutes to form the anion. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethylacetate (150 ml total) and the organic layers were combined and concentrated to give a yellow oil. Chromatographic purification on silica gel (chloroform/ethyl acetate gradient) gave 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.22 g, 9.65 mmol). MS (APCI+) 334 (M+1, 100); 1H NMR δ (400 MHz, DMSO-d6) 8.54 (s, 1H), 7.47-7.46 (m, 1H), 5.99-5.90 (m, 1H), 3.69 (t, J=6.25 Hz, 2H), 3.49 (q, J=7.03 Hz, 2H), 2.84 (t, J=6.25 Hz, 2H), 2.59 (s, 3H), 2.34-2.29 (m, 2H), 2.08-2.02 (m, 2H), 1.88-1.83 (m, 2H), 1.69-1.65 (m, 3H), 1.17 (t, J=7.04 Hz, 3H). to form the anion stirred overnight The reaction mixture was quenched with 10% aqueous HCl (100 ml) The aqueous layer was extracted with ethylacetate (150 ml total) concentrated to give a yellow oil Chromatographic purification on silica gel (chloroform/ethyl acetate gradient)

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

Procedure: To a cooled (−78° C.) solution of 4-ethoxy-butyric acid ethyl ester (9.85 g, 61.47 mmol) in THF (25 ml) was added lithium bis(trimethylsilyl)amide (77.0 ml, 76.85 mmol, 1 M solution in THF). The reaction mixture was stirred for 10 minutes to form the anion. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethylacetate (150 ml total) and the organic layers were combined and concentrated to give a yellow oil. Chromatographic purification on silica gel (chloroform/ethyl acetate gradient) gave 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.22 g, 9.65 mmol). MS (APCl+)334 (M+1, 100); 1H NMR δ(400 MHz, DMSO-d6) 8.54 (s, 1H), 7.47-7.46 (m, 1H), 5.99-5.90 (m, 1H), 3.69 (t, J=6.25 Hz, 2H), 3.49 (q, J=7.03 Hz, 2H), 2.84 (t, J=6.25 Hz, 2H), 2.59 (s, 3H), 2.34-2.29 (m, 2H), 2.08-2.02 (m, 2H), 1.88-1.83 (m, 2H), 1.69-1.65 (m, 3H), 1.17 (t, J=7.04 Hz, 3H). to form the anion stirred overnight The reaction mixture was quenched with 10% aqueous HCl (100 ml) The aqueous layer was extracted with ethylacetate (150 ml total) concentrated to give a yellow oil Chromatographic purification on silica gel (chloroform/ethyl acetate gradient)

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

Procedure: To a cooled (−78° C.) solution of 4-ethoxy-butyric acid ethyl ester (9.85 g, 61.47 mmol) in THF (25 ml) was added lithium bis(trimethylsilyl)amide (77.0 ml, 76.85 mmol, 1 M solution in THF). The reaction mixture was stirred for 10 minutes to form the anion. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethylacetate (150 ml total) and the organic layers were combined and concentrated to give a yellow oil. Chromatographic purification on silica gel (chloroform/ethyl acetate gradient) gave 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.22 g, 9.65 mmol). MS (APCI+) 334 (M+1, 100); 1H NMR δ (400 MHz, DMSO-d6) 8.54 (s, 1H), 7.47–7.46 (m, 1H), 5.99–5.90 (m, 1H), 3.69 (t, J=6.25 Hz, 2H), 3.49 (q, J=7.03 Hz, 2H), 2.84 (t, J=6.25 Hz, 2H), 2.59 (s, 3H), 2.34–2.29 (m, 2H), 2.08–2.02 (m, 2H), 1.88–1.83 (m, 2H), 1.69–1.65 (m, 3H), 1.17 (t, J=7.04 Hz, 3H). to form the anion stirred overnight The reaction mixture was quenched with 10% aqueous HCl (100 ml) The aqueous layer was extracted with ethylacetate (150 ml total) concentrated to give a yellow oil Chromatographic purification on silica gel (chloroform/ethyl acetate gradient)

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

Procedure: To an ice cold stirred solution of ethyl 4-ethoxybutanoate (30) (˜1 g) in 10 mL of tetrahydrofuran (THF) was added aqueous NaOH solution (0.62 g in 7 ml of H2O) and stirred at room temperature for 12 h, while monitoring the reaction by TLC. Most of the solvent was evaporated under reduced pressure and the residue was diluted with water (10 mL). The aqueous layer was acidified with 1N HCl solution (PH˜2) and then extracted with ethyl acetate (15 mL×3). The combined organic extracts was dried over anhydrous Na2SO4 and concentrated under vacuum to yield 0.6 g (73.14) of 4-ethoxybutanoic acid as light yellow oil. 1HNMR (400 MHz, CDCl3): δ 1.20 (t, J=9.2 Hz, 3H); 1.87-1.95 (m, 2H); 2.47 (t, J=10 Hz; 2H); 3.48 (q, J=9.2 Hz, 4H). the reaction by TLC Most of the solvent was evaporated under reduced pressure the residue was diluted with water (10 mL) extracted with ethyl acetate (15 mL×3) The combined organic extracts was dried over anhydrous Na2SO4 concentrated under vacuum

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sulfuric acid 0.25 mL (0.0045 mmol, 0.035 eq) was added to an ice cooled solution of γ-butyrolactone (28) (11.2 g, 0.13009 mmol, 1.0 eq), triethyl orthoformate (29) (41.1 mL, 0.2497 mmol., 1.92 eq) in 100 mL of ethanol. The mixture was heated at 50° C. for 12 h while monitoring the reaction by TLC. The reaction mixture was cooled to room temperature and most of the solvent was evaporated under reduced pressure. The concentrated reaction mixture was quenched with cold saturated NaHCO3 solution and extracted with ethyl acetate twice. The combined organic extracts was dried over anhydrous Na2SO4 and concentrated under vacuum to yielded 20 g (95%) of ethyl 4-ethoxybutanoate (30) as light yellow oil. 1HNMR (400 MHz, CDCl3): δ 1.16-1.28 (m, 6H); 1.87-1.91 (m, 2H); 2.39 (t, J=9.6 Hz; 2H); 3.42-3.50 (m, 2H); 3.57-3.64 (m, 2H); 4.13 (q, J=6 Hz, 2H). the reaction by TLC The reaction mixture was cooled to room temperature and most of the solvent was evaporated under reduced pressure The concentrated reaction mixture was quenched with cold saturated NaHCO3 solution extracted with ethyl acetate twice The combined organic extracts was dried over anhydrous Na2SO4 concentrated under vacuum

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

Procedure: To a cooled (−78° C.) solution of 4-ethoxy-butyric acid ethyl ester (9.85 g, 61.47 mmol) in THF (25 ml) was added lithium bis(trimethylsilyl)amide (77.0 ml, 76.85 mmol, 1 M solution in THF). The reaction mixture was stirred for 10 minutes to form the anion. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethylacetate (150 ml total) and the organic layers were combined and concentrated to give a yellow oil. Chromatographic purification on silica gel (chloroform/ethyl acetate gradient) gave 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.22 g, 9.65 mmol). MS (APCI+) 334 (M+1, 100); 1H NMR δ (400 MHz, DMSO-d6) 8.54 (s, 1H), 7.47-7.46 (m, 1H), 5.99-5.90 (m, 1H), 3.69 (t, J=6.25 Hz, 2H), 3.49 (q, J=7.03 Hz, 2H), 2.84 (t, J=6.25 Hz, 2H), 2.59 (s, 3H), 2.34-2.29 (m, 2H), 2.08-2.02 (m, 2H), 1.88-1.83 (m, 2H), 1.69-1.65 (m, 3H), 1.17 (t, J=7.04 Hz, 3H). to form the anion stirred overnight The reaction mixture was quenched with 10% aqueous HCl (100 ml) The aqueous layer was extracted with ethylacetate (150 ml total) concentrated to give a yellow oil Chromatographic purification on silica gel (chloroform/ethyl acetate gradient)