2,2-diethoxyethoxybenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (5.83 g of a 55% dispersion in mineral oil) was added to a solution of phenol (12.56 g) in DMPU (25 ml) at 5° C. and the mixture was stirred for 30 minutes. Bromoacetaldehyde diethyl acetal (10.05 ml) was added and the mixture was heated at 110° C. for 5 hours, then allowed to cool. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic phase was separated and washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml). The aqueous fractions were combined and re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried (MgSO4) and concentrated. The resultant oil was purified by flash column chromatography, eluting with ethyl acetate/hexane (1:10 v/v) to give 2-phenoxyacetaldehyde diethyl acetal (9.43 g) as an oil; NMR: 1.25(6H,t, J=7.0 Hz), 3.6-3.85(4H,m), 4.05(2 H,d, J=6.0 Hz), 4.85 (1H,t, J=6.0 Hz) and 6.9-7.35(5H,m). to cool The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) the organic phase was separated washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml) re-extracted with ethyl acetate (100 ml) The combined organic extracts were dried (MgSO4) concentrated The resultant oil was purified by flash column chromatography eluting with ethyl acetate/hexane (1:10 v/v)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: An appropriate phenol or substituted phenol (i.e., a compound suitable for forming the Y2 substituent of formula I) is reacted with a molar excess of chloroacetaldehyde diethyl acetal (ClCH2CH(OCH2CH3)2) in the presence of potassium hydroxide to form a phenoxyacetaldehyde diethyl acetal. This procedure is taught by Lipinski et al., J. Med. Chem., 23, 1026 (1980) which is incorporated herein by reference. The phenoxyacetaldehyde diethyl acetal is then added to a mixture containing POCl3 and DMF and heated for a period of time sufficient to form 2-(phenoxy)-3-dimethylamino-propenal which is then reacted with malonamide (i.e., CH2 (CONH2)2) in the presence of t-BuOK and DMSO. The desired, 5-(phenoxy-2-hydroxy-3-pyridinecarboxamide may then be collected by conventional techniques. The isolated pyridinecarboxamide is then added to phenylphosphonic dichloride followed by the addition of PCl5. The mixture is heated and the desired 5-(phenoxy)-2-chloro-3-pyridinecarbonitrile is isolated. This product may then be treated with the desired alkylmercaptan in NaOH to form the 5-(phenoxy)-2-(R-thio)- 3-pyridinecarbonitrile which may then be oxidized to the R-sulfinyl or R-sulfonyl form and/or to the 3-pyridinecarboxamide compound if desired. heated for a period of time sufficient

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (5.83 g of a 55% dispersion in mineral oil) was added to a solution of phenol (12.56 g) in DMPU (25 ml) at 5° C. and the mixture was stirred for 30 minutes. Bromoacetaldehyde diethyl acetal (10.05 ml) was added and the mixture was heated at 110° C. for 5 hours, then allowed to cool. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic phase was separated and washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml). The aqueous fractions were combined and re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried (MgSO4) and concentrated. The resultant oil was purified by flash column chromatography, eluting with ethyl acetate/hexane (1:10 v/v) to give 2-phenoxyacetaldehyde diethyl acetal (9.43 g) as an oil; NMR: 1.25(6H,t, J=7.0 Hz), 3.6-3.85(4H,m), 4.05(2 H,d, J=6.0 Hz), 4.85 (1H,t, J=6.0 Hz) and 6.9-7.35(5H,m). to cool The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) the organic phase was separated washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml) re-extracted with ethyl acetate (100 ml) The combined organic extracts were dried (MgSO4) concentrated The resultant oil was purified by flash column chromatography eluting with ethyl acetate/hexane (1:10 v/v)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (5.83 g of a 55% dispersion in mineral oil) was added to a solution of phenol (12.56 g) in DMPU (25 ml) at 5° C. and the mixture was stirred for 30 minutes. Bromoacetaldehyde diethyl acetal (10.05 ml) was added and the mixture was heated at 110° C. for 5 hours, then allowed to cool. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic phase was separated and washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml). The aqueous fractions were combined and re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried (MgSO4) and concentrated. The resultant oil was purified by flash column chromatography, eluting with ethyl acetate/hexane (1:10 v/v) to give 2-phenoxyacetaldehyde diethyl acetal (9.43 g) as an oil; NMR: 1.25(6H,t, J=7.0 Hz), 3.6-3.85(4H,m), 4.05(2 H,d, J=6.0 Hz), 4.85 (1H,t, J=6.0 Hz) and 6.9-7.35(5H,m). to cool The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) the organic phase was separated washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml) re-extracted with ethyl acetate (100 ml) The combined organic extracts were dried (MgSO4) concentrated The resultant oil was purified by flash column chromatography eluting with ethyl acetate/hexane (1:10 v/v)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (5.83 g of a 55% dispersion in mineral oil) was added to a solution of phenol (12.56 g) in DMPU (25 ml) at 5° C. and the mixture was stirred for 30 minutes. Bromoacetaldehyde diethyl acetal (10.05 ml) was added and the mixture was heated at 110° C. for 5 hours, then allowed to cool. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic phase was separated and washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml). The aqueous fractions were combined and re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried (MgSO4) and concentrated. The resultant oil was purified by flash column chromatography, eluting with ethyl acetate/hexane (1:10 v/v) to give 2-phenoxyacetaldehyde diethyl acetal (9.43 g) as an oil; NMR: 1.25(6H,t, J=7.0 Hz), 3.6-3.85(4H,m), 4.05(2 H,d, J=6.0 Hz), 4.85 (1H,t, J=6.0 Hz) and 6.9-7.35(5H,m). to cool The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) the organic phase was separated washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml) re-extracted with ethyl acetate (100 ml) The combined organic extracts were dried (MgSO4) concentrated The resultant oil was purified by flash column chromatography eluting with ethyl acetate/hexane (1:10 v/v)

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

Procedure: 0.84 g (4 mmol) of 69A, 5 mL of acetic acid, 2.5 mL of 1N aqueous hydrochloric acid and 20 mL of ethanol were mixed and heated under reflux under an argon atmosphere for 3 hours. Ethanol was evaporated. Then the resulting residue was dispersed in dichloromethane and extracted with saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and the solvent evaporated in vacuum. The crude product was obtained in almost quantitative yield. heated under reflux under an argon atmosphere for 3 hours Ethanol was evaporated Then the resulting residue was dispersed in dichloromethane extracted with saturated sodium bicarbonate solution The organic phase was dried with sodium sulfate the solvent evaporated in vacuum

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

Procedure: 0.94 g (10 mmol) of phenol, 1.52 g (10 mmol) of chloroacetaldehyde diethyl acetal, 2.77 g (20 mmol) of potassium carbonate, 500 mg of potassium iodide and 5 ml of dimethylformamide were heated for 1 hour at 175° C. under microwave conditions. The mixture was then diluted with 2M aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried with sodium sulfate and the solvent evaporated in vacuum. The crude product was obtained in almost quantitative yield. extracted with dichloromethane The organic layer was dried with sodium sulfate the solvent evaporated in vacuum

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (5.83 g of a 55% dispersion in mineral oil) was added to a solution of phenol (12.56 g) in DMPU (25 ml) at 5° C. and the mixture was stirred for 30 minutes. Bromoacetaldehyde diethyl acetal (10.05 ml) was added and the mixture was heated at 110° C. for 5 hours, then allowed to cool. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic phase was separated and washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml). The aqueous fractions were combined and re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried (MgSO4) and concentrated. The resultant oil was purified by flash column chromatography, eluting with ethyl acetate/hexane (1:10 v/v) to give 2-phenoxyacetaldehyde diethyl acetal (9.43 g) as an oil; NMR: 1.25(6H,t, J=7.0 Hz), 3.6-3.85(4H,m), 4.05(2 H,d, J=6.0 Hz), 4.85 (1H,t, J=6.0 Hz) and 6.9-7.35(5H,m). to cool The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) the organic phase was separated washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml) re-extracted with ethyl acetate (100 ml) The combined organic extracts were dried (MgSO4) concentrated The resultant oil was purified by flash column chromatography eluting with ethyl acetate/hexane (1:10 v/v)

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

Procedure: An appropriate phenol or substituted phenol (i.e., a compound suitable for forming the Y2 substituent of formula I) is reacted with a molar excess of chloroacetaldehyde diethyl acetal (ClCH2CH(OCH2CH3)2) in the presence of potassium hydroxide to form a phenoxyacetaldehyde diethyl acetal. This procedure is taught by Lipinski et al., J. Med. Chem., 23, 1026 (1980) which is incorporated herein by reference. The phenoxyacetaldehyde diethyl acetal is then added to a mixture containing POCl3 and DMF and heated for a period of time sufficient to form 2-(phenoxy)-3-dimethylamino-propenal which is then reacted with malonamide (i.e., CH2 (CONH2)2) in the presence of t-BuOK and DMSO. The desired, 5-(phenoxy-2-hydroxy-3-pyridinecarboxamide may then be collected by conventional techniques. The isolated pyridinecarboxamide is then added to phenylphosphonic dichloride followed by the addition of PCl5. The mixture is heated and the desired 5-(phenoxy)-2-chloro-3-pyridinecarbonitrile is isolated. This product may then be treated with the desired alkylmercaptan in NaOH to form the 5-(phenoxy)-2-(R-thio)- 3-pyridinecarbonitrile which may then be oxidized to the R-sulfinyl or R-sulfonyl form and/or to the 3-pyridinecarboxamide compound if desired. heated for a period of time sufficient