methyl 2-[4-(hydroxymethyl)phenoxy]acetate

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: 18.2 g of 4-hydroxymethylphenoxyacetic acid are dissolved together with 17.1 ml of N,N-diisopropylethylamine in 50 ml of DMF, and then 6.1 ml of methyl iodide are added to the stirred solution. The mixture warms slightly during this. The reaction is complete after 3 h. The solvent is removed in vacuo. The residue is taken up in ether, and the solution is extracted once with 0.5 N hydrochloric acid. The aqueous phase is then extracted three times with ether, and the combined ether phases are washed with aqueous sodium bicarbonate solution and concentrated. The residue is dissolved in ethyl acetate and filtered through a short silica gel column. The pale yellowish oil which is obtained after concentration crystallizes on being left to stand. The solvent is removed in vacuo the solution is extracted once with 0.5 N hydrochloric acid The aqueous phase is then extracted three times with ether the combined ether phases are washed with aqueous sodium bicarbonate solution concentrated The residue is dissolved in ethyl acetate filtered through a short silica gel column The pale yellowish oil which is obtained after concentration crystallizes on being left

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: A solution of (4-hydroxymethyl-phenoxy)-acetic acid methyl ester 69 (100 grams, 509 mmol), acetic anhydride (250 mL) and pyridine (20 mL) was refluxed for 4 hours. Reaction mixture was poured in to ice water (1000 mL) and crude 70 was extracted into chloroform, dried over Na2SO4, and distilled. The crude was vacuum distilled to give pure 70 (75 grams, 61.7%) as a light yellow syrup, Bp15 206-210° C. The structure was confirmed with NMR. IHNMR (CDCl3) δ 2.05 (s, 3H,O═C—CH3), 3.78(s, 3H,ester), 4.62(s, 2H,OCH2), 5.02 (s, 2H, CH2), 6.88 (d,2H,Ar), 7.33 (d, 2H,Ar). Reaction mixture was extracted into chloroform dried over Na2SO4 distilled distilled

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

Procedure: A solution of (4-hydroxymethyl-phenoxy)-acetic acid methyl ester 69 (100 grams, 509 mmol), acetic anhydride (250 mL) and pyridine (20 mL) was refluxed for 4 hours. Reaction mixture was poured in to ice water (1000 mL) and crude 70 was extracted into chloroform, dried over Na2SO4, and distilled. The crude was vacuum distilled to give pure 70 (75 grams, 61.7%) as a light yellow syrup, Bp15 206-210° C. The structure was confirmed with NMR. IHNMR (CDCl3) δ 2.05 (s, 3H,O═C—CH3), 3.78(s, 3H,ester), 4.62(s, 2H,OCH2), 5.02 (s, 2H, CH2), 6.88 (d,2H,Ar), 7.33 (d, 2H,Ar). Reaction mixture was extracted into chloroform dried over Na2SO4 distilled distilled

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

Procedure: To a solution of (4-Formylphenoxy)acetic acid methyl ester 68 (160 grams, 825 mmol) in methanol (800 mL) at 0° C. was added Sodium borohydrate (18 grams, 476 mmol) in small portions, further stirred at 0° C. for 2 hours and poured on to ice water (1500 mL). The pH of mixture was adjusted to 2 with concentrated hydrochloric acid. Crude 69 was extracted into chloroform, dried over Na2SO4, distilled and purified by column chromatography on silica gel using hexane:ethyl acetate (7:3) to give 69 (100 grams, 62%) as white powder Crude 69 was extracted into chloroform dried over Na2SO4 distilled purified by column chromatography on silica gel

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

Procedure: To a solution of (4-Formylphenoxy)acetic acid methyl ester 68 (160 grams, 825 mmol) in methanol (800 mL) at 0° C. was added Sodium borohydrate (18 grams, 476 mmol) in small portions, further stirred at 0° C. for 2 hours and poured on to ice water (1500 mL). The pH of mixture was adjusted to 2 with concentrated hydrochloric acid. Crude 69 was extracted into chloroform, dried over Na2SO4, distilled and purified by column chromatography on silica gel using hexane:ethyl acetate (7:3) to give 69 (100 grams, 62%) as white powder Crude 69 was extracted into chloroform dried over Na2SO4 distilled purified by column chromatography on silica gel

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

Procedure: To a solution of 4.00 g (20.4 mmol) of the product of Step A dissolved in 30 mL of CH2Cl2 was added 5.00 g (40.8 mmol) of 4-dimethylaminopyridine and 3.69 g (24.5 mmol) of tert-butyldimethylchlorosilane and the mixture was stirred under N2 for 5 hours. The reaction mixture was then filtered and the filtrate was diluted with ethyl acetate. The solution was washed with water, 1N HCl, saturated NaHCO3, dried (MgSO4), filtered and evaporated. Drying in vacuo afforded 6.30 g (99%) of the title compound. The reaction mixture was then filtered the filtrate was diluted with ethyl acetate The solution was washed with water, 1N HCl, saturated NaHCO3 dried (MgSO4) filtered evaporated Drying in vacuo

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

Procedure: To a solution of 4.00 g (20.4 mmol) of the product of Step A dissolved in 30 mL of CH2Cl2 was added 5.00 g (40.8 mmol) of 4-dimethylaminopyridine and 3.69 g (24.5 mmol) of tert-butyldimethylchlorosilane and the mixture was stirred under N2 for 5 hours. The reaction mixture was then filtered and the filtrate was diluted with ethyl acetate. The solution was washed with water, 1N HCl, saturated NaHCO3, dried (MgSO4), filtered and evaporated. Drying in vacuo afforded 6.30 g (99%) of the title compound. The reaction mixture was then filtered the filtrate was diluted with ethyl acetate The solution was washed with water, 1N HCl, saturated NaHCO3 dried (MgSO4) filtered evaporated Drying in vacuo

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

Procedure: Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 8.00 g (64.5. mmol) of 4-hydroxybenzyl alcohol was alkylated with 11.84 g (77.4 mmol) of methyl bromoacetate to afford 6.00 g (48%) of the title compound.