ethyl 4-[4-(hydroxymethyl)phenoxy]butanoate

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

Procedure: 4-Hydroxybenzyl alcohol (1 g, 8.06 mmol) is treated with 1.73 g (8.86 mmol) of ethyl 4-bromobutyrate, 3.34 g (24.2 mmol) of potassium carbonate and a catalytic amount (120 mg 0.81 mmol) of sodium iodide under the same conditions as described in Preparation 3 to give 1.73 g of 4-[4-(hydroxymethyl)phenoxy]butanoic acid, ethyl ester as a light brown oil (90%). The product is utilized in the next reaction without further purification. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3400, 1730, 1610, 1580, 1510 cm-1 ; MS (CI) m/e 238, 221, 115.

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

Procedure: 4-Hydroxybenzyl alcohol (1 g, 8.06 mmol) is treated with 1.73 g (8.86 mmol) of ethyl 4-bromobutyrate, 3.34 g (24.2 mmol) of potassium carbonate and a catalytic amount (120 mg 0.81 mmol) of sodium iodide under the same conditions as described in Preparation 3 to give 1.73 g of 4-[4-(hydroxymethyl)phenoxy]butanoic acid, ethyl ester as a light brown oil (90%). The product is utilized in the next reaction without further purification. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3400, 1730, 1610, 1580, 1510 cm-1 ; MS (CI) m/e 238, 221, 115.

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

Procedure: Ethyl 4-(4-(chloromethyl)phenoxy)butanoate 13i was prepared from 29b according to the protocol described for the compound 13h in Example 26 (Scheme 9). The title chloride 13i was isolated as colorless oil in 96% yield (1.25 g). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz); 2.06 (2H, m); 2.18 (2H, t, J=7.2 Hz)); 4.00 (2H, t, J=6.4 Hz); 4.14 (2H, q, J=7.2 Hz); 4.54 (2H, s); 6.83 (1H, s); 6.86 (1H, s); 7.27 (1H, m); 7.29 (1H, s). MS (ESI): m/z=258.10 (M+H+).

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

Procedure: Ethyl 4-(4-(chloromethyl)phenoxy)butanoate 13i was prepared from 29b according to the protocol described for the compound 13h in Example 26 (Scheme 9). The title chloride 13i was isolated as colorless oil in 96% yield (1.25 g). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz); 2.06 (2H, m); 2.18 (2H, t, J=7.2 Hz)); 4.00 (2H, t, J=6.4 Hz); 4.14 (2H, q, J=7.2 Hz); 4.54 (2H, s); 6.83 (1H, s); 6.86 (1H, s); 7.27 (1H, m); 7.29 (1H, s). MS (ESI): m/z=258.10 (M+H+).

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

Procedure: Ethyl 4-(4-(hydroxymethyl)phenoxy)butanoate 29b was prepared by reacting 4-(hydroxymethyl)phenol 27b with ethyl 4-bromobutyrate 28b according to protocol described for the compound 29a in Example 24 (Scheme 9). The ester 29b was isolated as colorless oil 96% yield (2.26 g). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz); 2.07 (2H, m); 2.15 (2H, t, J=7.2 Hz)); 3.97 (2H, t, J=6.4 Hz); 4.10 (2H, q, J=7.2 Hz); 4.59 (2H, s); 6.88 (1H, s); 6.87 (1H, s); 7.24-7.27 (2H, m). Ethyl 4-(4-(hydroxymethyl)phenoxy)butanoate 29b was prepared

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

Procedure: Ethyl 4-(4-(chloromethyl)phenoxy)butanoate 13i was prepared from 29b according to the protocol described for the compound 13h in Example 26 (Scheme 9). The title chloride 13i was isolated as colorless oil in 96% yield (1.25 g). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz); 2.06 (2H, m); 2.18 (2H, t, J=7.2 Hz)); 4.00 (2H, t, J=6.4 Hz); 4.14 (2H, q, J=7.2 Hz); 4.54 (2H, s); 6.83 (1H, s); 6.86 (1H, s); 7.27 (1H, m); 7.29 (1H, s). MS (ESI): m/z=258.10 (M+H+).

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

Procedure: Ethyl 4-(4-(hydroxymethyl)phenoxy)butanoate 29b was prepared by reacting 4-(hydroxymethyl)phenol 27b with ethyl 4-bromobutyrate 28b according to protocol described for the compound 29a in Example 24 (Scheme 9). The ester 29b was isolated as colorless oil 96% yield (2.26 g). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz); 2.07 (2H, m); 2.15 (2H, t, J=7.2 Hz)); 3.97 (2H, t, J=6.4 Hz); 4.10 (2H, q, J=7.2 Hz); 4.59 (2H, s); 6.88 (1H, s); 6.87 (1H, s); 7.24-7.27 (2H, m). Ethyl 4-(4-(hydroxymethyl)phenoxy)butanoate 29b was prepared

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

Procedure: To a solution of the intermediate from step B (1 g, 4.24 mmol) in acetonitrile was added triphenyl phosphine (1.45 g, 5.5 mmol), imidazole (0.4 g, 5.93 mmol) and iodine (1.51 g, 5.94 mmol). After 20 minutes, the reaction was quenched with saturated Na2S2O3 solution. The resulting mixture was extracted with ethyl acetate washed with brine and dried over anhydrous Na2SO4. The solution was filtered, concentrated in vacuo and purified by flash chromatography using 15% ethyl acetate-hexanes to give the desired product as an oil. 1H NMR (CDCl3, 500 MHz): 7.32 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 4.48 (s, 2H), 4.18 (q, J=6.1 Hz, 2H), 4.01 (t, J=6.1 Hz, 2H), 2.53 (t, J=7.4 Hz, 2H), 2.14 (m, 2H), 1.29 (t, J=7.1 Hz, 3H). LC-MS=2.36 min; (M+23)=371.0. the reaction was quenched with saturated Na2S2O3 solution The resulting mixture was extracted with ethyl acetate washed with brine dried over anhydrous Na2SO4 The solution was filtered concentrated in vacuo purified by flash chromatography

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

Procedure: 4-Hydroxybenzyl alcohol (1 g, 8.06 mmol) is treated with 1.73 g (8.86 mmol) of ethyl 4-bromobutyrate, 3.34 g (24.2 mmol) of potassium carbonate and a catalytic amount (120 mg 0.81 mmol) of sodium iodide under the same conditions as described in Preparation 3 to give 1.73 g of 4-[4-(hydroxymethyl)phenoxy]butanoic acid, ethyl ester as a light brown oil (90%). The product is utilized in the next reaction without further purification. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3400, 1730, 1610, 1580, 1510 cm-1 ; MS (CI) m/e 238, 221, 115.

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

Procedure: 4-Hydroxybenzyl alcohol (1 g, 8.06 mmol) is treated with 1.73 g (8.86 mmol) of ethyl 4-bromobutyrate, 3.34 g (24.2 mmol) of potassium carbonate and a catalytic amount (120 mg 0.81 mmol) of sodium iodide under the same conditions as described in Preparation 3 to give 1.73 g of 4-[4-(hydroxymethyl)phenoxy]butanoic acid, ethyl ester as a light brown oil (90%). The product is utilized in the next reaction without further purification. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3400, 1730, 1610, 1580, 1510 cm-1 ; MS (CI) m/e 238, 221, 115.

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

Procedure: 4-Hydroxybenzyl alcohol (1 g, 8.06 mmol) is treated with 1.73 g (8.86 mmol) of ethyl 4-bromobutyrate, 3.34 g (24.2 mmol) of potassium carbonate and a catalytic amount (120 mg 0.81 mmol) of sodium iodide under the same conditions as described in Preparation 3 to give 1.73 g of 4-[4-(hydroxymethyl)phenoxy]butanoic acid, ethyl ester as a light brown oil (90%). The product is utilized in the next reaction without further purification. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3400, 1730, 1610, 1580, 1510 cm-1 ; MS (CI) m/e 238, 221, 115.

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

Procedure: 4-Hydroxybenzyl alcohol (1 g, 8.06 mmol) is treated with 1.73 g (8.86 mmol) of ethyl 4-bromobutyrate, 3.34 g (24.2 mmol) of potassium carbonate and a catalytic amount (120 mg 0.81 mmol) of sodium iodide under the same conditions as described in Preparation 3 to give 1.73 g of 4-[4-(hydroxymethyl)phenoxy]butanoic acid, ethyl ester as a light brown oil (90%). The product is utilized in the next reaction without further purification. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3400, 1730, 1610, 1580, 1510 cm-1 ; MS (CI) m/e 238, 221, 115.