2-(4-hydroxy-3-methoxyphenyl)acetonitrile

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Hydroxy-3-methoxyphenyl)acetonitrile (0.54 g, 3.31 mmol) in THF (10 mL) was treated with 3-cyclopentylpropan-1-ol (0.424 g, 3.31 mmol), triphenylphosphine (1.128 g, 4.3 mmol) and cooled in an ice bath to 0° C. DIAD (0.785 ml, 4 mmol) was added to the reaction mixture dropwise over the period of 5 min, and the reaction was left stirring slowly warming to room temperature over 18 hours. The reaction mixture was concentrated. Purification by flash chromatography (silica gel, 0-40% EtOAc/hexanes) afforded 0.871 g (96%) of 2-(4-(3-cyclopentylpropoxy)-3-methoxyphenyl)acetonitrile. MS (ESI) m/z 274 (M+H)+ the reaction was left warming to room temperature over 18 hours The reaction mixture was concentrated Purification by flash chromatography (silica gel, 0-40% EtOAc/hexanes)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Hydroxy-3-methoxyphenyl)acetonitrile (0.54 g, 3.31 mmol) in THF (10 mL) was treated with 3-cyclopentylpropan-1-ol (0.424 g, 3.31 mmol), triphenylphosphine (1.128 g, 4.3 mmol) and cooled in an ice bath to 0° C. DIAD (0.785 ml, 4 mmol) was added to the reaction mixture dropwise over the period of 5 min, and the reaction was left stirring slowly warming to room temperature over 18 hours. The reaction mixture was concentrated. Purification by flash chromatography (silica gel, 0-40% EtOAc/hexanes) afforded 0.871 g (96%) of 2-(4-(3-cyclopentylpropoxy)-3-methoxyphenyl)acetonitrile. MS (ESI) m/z 274 (M+H)+ the reaction was left warming to room temperature over 18 hours The reaction mixture was concentrated Purification by flash chromatography (silica gel, 0-40% EtOAc/hexanes)

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

Procedure: A mixture of 15 grams 4-hydroxy-3-methoxyphenylacetonitrile (91.91 mmol), 26.40 ml (33.59 grams) n-butyl bromide (245 mmol) and 21.17 grams potassium carbonate (153.2 mmol) in 150 ml acetone was heated to reflux under nitrogen for 18 hours. After cooling to room temperature, the mixture was diluted with diethyl ether and the inorganic salts were removed by filtration and were washed with diethyl ether. The filtrate and wash solutions were evaporated in vacuo to provide 21.11 grams of Compound 10c as a straw-colored viscous oil (99.9% yield) which was dried in vacuo at 50° C. was heated to reflux under nitrogen for 18 hours the inorganic salts were removed by filtration were washed with diethyl ether The filtrate and wash solutions were evaporated in vacuo

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

Procedure: A mixture of 15 grams 4-hydroxy-3-methoxyphenylacetonitrile (91.91 mmol), 26.40 ml (33.59 grams) n-butyl bromide (245 mmol) and 21.17 grams potassium carbonate (153.2 mmol) in 150 ml acetone was heated to reflux under nitrogen for 18 hours. After cooling to room temperature, the mixture was diluted with diethyl ether and the inorganic salts were removed by filtration and were washed with diethyl ether. The filtrate and wash solutions were evaporated in vacuo to provide 21.11 grams of Compound 10c as a straw-colored viscous oil (99.9% yield) which was dried in vacuo at 50° C. was heated to reflux under nitrogen for 18 hours the inorganic salts were removed by filtration were washed with diethyl ether The filtrate and wash solutions were evaporated in vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-hydroxy-3-methoxyphenylacetonitrile (150 g, 0.919 mol) in phosphoric acid 85% (877 mL, 15.000 mol) was added 4-chlorobenzaldehyde (168 g, 1.195 mol), then the reaction mixture was heated at 120° C. for 2 h. After cooling to 90° C., the reaction mixture was slowly poured into the stirred 4 L of iced water. Resulting suspension was stirred at RT for 2 h, then filtered and washed with 500 ml of water 4 times. Crude and wet material was stirred in acetonitrile (1 L) at RT for 1 h, then filtration and dry up gave the title intermediate (163.6 g, 0.539 mol, 58.6%). HPLC: EtRet=4.20 min; LC-MS: m/z 304.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): δ 3.25-3.53 (m, 2H), 3.72 (s, 3H), 5.47 (d, J=3.12 Hz, 1H), 6.53 (s, 1H), 6.72 (s, 1H), 7.24 (d, 2H), 7.37 (d, 2H), 8.42 (d, J=3.51 Hz, 1H), 8.86 (br. s., 1H). After cooling to 90° C. Resulting suspension filtered washed with 500 ml of water 4 times Crude and wet material was stirred in acetonitrile (1 L) at RT for 1 h filtration dry up

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11.0 g (67 mmol) of [4-hydroxy-3-methoxy-phenyl]acetonitrile and 20.4 g (81 mmol) of 11-bromoundecan-1-ol were dissolved in 100 mL of N,N-dimethylformamide. 18.7 g (135 mmol) of potassium carbonate and 2.2.0 g (13 mmol) of potassium iodide were added and the suspension was heated to 80° C. After 48 h, the reaction mixture was cooled to room temperature and poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine and evaporated to dryness. The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) and dried overnight at 40° C. 16.6 g of {4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}acetonitrile are obtained as a yellow solid (74% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure. the reaction mixture was cooled to room temperature The aqueous layer is extracted twice with ethyl acetate Combined organic layers are washed with brine evaporated to dryness The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) dried overnight at 40° C

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11.0 g (67 mmol) of [4-hydroxy-3-methoxy-phenyl]acetonitrile and 20.4 g (81 mmol) of 11-bromoundecan-1-ol were dissolved in 100 mL of N,N-dimethylformamide. 18.7 g (135 mmol) of potassium carbonate and 2.2.0 g (13 mmol) of potassium iodide were added and the suspension was heated to 80° C. After 48 h, the reaction mixture was cooled to room temperature and poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine and evaporated to dryness. The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) and dried overnight at 40° C. 16.6 g of {4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}acetonitrile are obtained as a yellow solid (74% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure. the reaction mixture was cooled to room temperature The aqueous layer is extracted twice with ethyl acetate Combined organic layers are washed with brine evaporated to dryness The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) dried overnight at 40° C

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-hydroxy-3-methoxyphenylacetonitrile (150 g, 0.919 mol) in phosphoric acid 85% (877 mL, 15.000 mol) was added 4-chlorobenzaldehyde (168 g, 1.195 mol), then the reaction mixture was heated at 120° C. for 2 h. After cooling to 90° C., the reaction mixture was slowly poured into the stirred 4 L of iced water. Resulting suspension was stirred at RT for 2 h, then filtered and washed with 500 mL of water 4 times. Crude and wet material was stirred in acetonitrile (1 L) at RT for 1 h, then filtration and dry up gave the title intermediate (163.6 g, 0.539 mol, 58.6%). HPLC: EtRet=4.20 min; LC-MS: m/z 304.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 3.25-3.53 (m, 2H), 3.72 (s, 3H), 5.47 (d, J=3.12 Hz, 1H), 6.53 (s, 1H), 6.72 (s, 1H), 7.24 (d, 2H), 7.37 (d, 2H), 8.42 (d, J=3.51 Hz, 1H), 8.86 (br. s., 1H). After cooling to 90° C. Resulting suspension filtered washed with 500 mL of water 4 times Crude and wet material was stirred in acetonitrile (1 L) at RT for 1 h filtration dry up