(2R)-3-phenylmethoxypropane-1,2-diol

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

Procedure: A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0 mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and 1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH2Cl2 (120 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2). The combined organic extracts were back washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers (88:12, 3.87 g). 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.40-7.03 (m, 8H), 5.34 (s, 2H), 4.17-4.14 (m, 2H), 3.88 (s, 3H), 3.9-3.85 (m, 2H), 3.33-3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2, 128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5, 73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS) m/z 412 (M+NH4)+. The byproduct, dicyclohexyl urea, was removed by filtration The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2) The combined organic extracts were back washed with water, brine dried over Na2SO4 filtered concentrated dried under vacuum The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give

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

Procedure: A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0 mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and 1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH2Cl2 (120 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2). The combined organic extracts were back washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers (88:12, 3.87 g). 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.40-7.03 (m, 8H), 5.34 (s, 2H), 4.17-4.14 (m, 2H), 3.88 (s, 3H), 3.9-3.85 (m, 2H), 3.33-3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2, 128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5, 73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS) m/z 412 (M+NH4)+. The byproduct, dicyclohexyl urea, was removed by filtration The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2) The combined organic extracts were back washed with water, brine dried over Na2SO4 filtered concentrated dried under vacuum The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give

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

Procedure: (2R)-3-(benzyloxy)propane-1,2-diol (2.00 g, 11.0 mmol) and tetrabutylammonium bromide (708 mg, 2.20 mmol) were dissolved in 50 mL of 1,2-dichloroethane, then 50 mL of a 50% (w/w) aqueous sodium hydroxide solution was added quickly and the mixture was heated to 50° C. After 18 h, an additional 50 mL of 1,2-dichloroethane and 50 mL of 50% (w/w) sodium hydroxide solution was added. After 8 h, additional 50 mL of 1,2-dichloroethane was added. After 72 h, the mixture was diluted in diethyl ether, washed with water and brine, then dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, ethylacetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 7.26-7.35 (m, 5H); 4.51-4.56 (m, 2H); 3.72-3.82 (m, 4H); 3.67-3.71 (m, 1H); 3.58-3.64 (m, 1H); 3.38-3.48 (m, 3H). After 8 h After 72 h washed with water and brine dried over sodium sulfate concentrated The residue was purified by flash column chromatography (silica, ethylacetate/hexanes)

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

Procedure: To a solution of (R)-3-benzyloxypropane-1,2-diol (prepared from (S)-4-benzylymethyl-2,2-dimethyl-1,3-dioxolane (commercially available from FLUKA) by acid hydrolysis using 80% aqueous acetic acid), (8.3 g, 47.2 mmol) in dry THF (70 ml) was added imidazole (6.42 g, 94.4 mmol). After 2 minutes, t-butyldiphenylsilyl chloride (12.28 ml, 47.2 mmol) was added. A white precipitate formed immediately. After 2 hours, the reaction mixture was filtered and the filtrate evaporated. The residue was partitioned between ethyl acetate and water, the organic layer separated, washed with saturated brine, dried (MgSO4), filtered and evaporated to give a colourless oil. Chromatography of the oil on silica gel (dichloromethane as eluant) afforded the title compound as a colourless oil (17.72 g, 90%). by acid hydrolysis A white precipitate formed immediately After 2 hours the reaction mixture was filtered the filtrate evaporated The residue was partitioned between ethyl acetate and water the organic layer separated washed with saturated brine dried (MgSO4) filtered evaporated to give a colourless oil

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

Procedure: (2R)-3-(benzyloxy)propane-1,2-diol (2.00 g, 11.0 mmol) and tetrabutylammonium bromide (708 mg, 2.20 mmol) were dissolved in 50 mL of 1,2-dichloroethane, then 50 mL of a 50% (w/w) aqueous sodium hydroxide solution was added quickly and the mixture was heated to 50° C. After 18 h, an additional 50 mL of 1,2-dichloroethane and 50 mL of 50% (w/w) sodium hydroxide solution was added. After 8 h, additional 50 mL of 1,2-dichloroethane was added. After 72 h, the mixture was diluted in diethyl ether, washed with water and brine, then dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, ethylacetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 7.26-7.35 (m, 5H); 4.51-4.56 (m, 2H); 3.72-3.82 (m, 4H); 3.67-3.71 (m, 1H); 3.58-3.64 (m, 1H); 3.38-3.48 (m, 3H). After 8 h After 72 h washed with water and brine dried over sodium sulfate concentrated The residue was purified by flash column chromatography (silica, ethylacetate/hexanes)

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

Procedure: To a solution of (R)-3-benzyloxypropane-1,2-diol (prepared from (S)-4-benzylymethyl-2,2-dimethyl-1,3-dioxolane (commercially available from FLUKA) by acid hydrolysis using 80% aqueous acetic acid), (8.3 g, 47.2 mmol) in dry THF (70 ml) was added imidazole (6.42 g, 94.4 mmol). After 2 minutes, t-butyldiphenylsilyl chloride (12.28 ml, 47.2 mmol) was added. A white precipitate formed immediately. After 2 hours, the reaction mixture was filtered and the filtrate evaporated. The residue was partitioned between ethyl acetate and water, the organic layer separated, washed with saturated brine, dried (MgSO4), filtered and evaporated to give a colourless oil. Chromatography of the oil on silica gel (dichloromethane as eluant) afforded the title compound as a colourless oil (17.72 g, 90%). by acid hydrolysis A white precipitate formed immediately After 2 hours the reaction mixture was filtered the filtrate evaporated The residue was partitioned between ethyl acetate and water the organic layer separated washed with saturated brine dried (MgSO4) filtered evaporated to give a colourless oil

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

Procedure: To a solution of (R)-3-(benzyloxy)propane-1,2-diol (1 eq) in THF (0.3 M) was added n-tetrabutylammonium bromide (0.2 eq), 1-bromododecane (4 eq) and potassium hydroxide (5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl ether, washed with water, 1 N hydrochloric acid, water, and brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give the product. washed with water, 1 N hydrochloric acid, water, and brine dried over anhydrous Na2SO4 concentrated en vaccuo The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) to give the product

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

Procedure: To a solution of (R)-3-(benzyloxy)propane-1,2-diol (1 eq) in THF (0.3 M) was added n-tetrabutylammonium bromide (0.2 eq), 1-bromododecane (4 eq) and potassium hydroxide (5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl ether, washed with water, 1 N hydrochloric acid, water, and brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give the product. washed with water, 1 N hydrochloric acid, water, and brine dried over anhydrous Na2SO4 concentrated en vaccuo The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) to give the product

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

Procedure: A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0 mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and 1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH2Cl2 (120 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2). The combined organic extracts were back washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers (88:12, 3.87 g). 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.40-7.03 (m, 8H), 5.34 (s, 2H), 4.17-4.14 (m, 2H), 3.88 (s, 3H), 3.9-3.85 (m, 2H), 3.33-3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2, 128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5, 73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS) m/z 412 (M+NH4)+. The byproduct, dicyclohexyl urea, was removed by filtration The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2) The combined organic extracts were back washed with water, brine dried over Na2SO4 filtered concentrated dried under vacuum The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give

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

Procedure: A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0 mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and 1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH2Cl2 (120 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2). The combined organic extracts were back washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers (88:12, 3.87 g). 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.40-7.03 (m, 8H), 5.34 (s, 2H), 4.17-4.14 (m, 2H), 3.88 (s, 3H), 3.9-3.85 (m, 2H), 3.33-3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2, 128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5, 73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS) m/z 412 (M+NH4)+. The byproduct, dicyclohexyl urea, was removed by filtration The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2) The combined organic extracts were back washed with water, brine dried over Na2SO4 filtered concentrated dried under vacuum The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give

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

Procedure: A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0 mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and 1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH2Cl2 (120 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2). The combined organic extracts were back washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers (88:12, 3.87 g). 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.40-7.03 (m, 8H), 5.34 (s, 2H), 4.17-4.14 (m, 2H), 3.88 (s, 3H), 3.9-3.85 (m, 2H), 3.33-3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2, 128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5, 73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS) m/z 412 (M+NH4)+. The byproduct, dicyclohexyl urea, was removed by filtration The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2) The combined organic extracts were back washed with water, brine dried over Na2SO4 filtered concentrated dried under vacuum The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give

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

Procedure: To a solution of (R)-3-(benzyloxy)propane-1,2-diol (1 eq) in THF (0.3 M) was added n-tetrabutylammonium bromide (0.2 eq), 1-bromododecane (4 eq) and potassium hydroxide (5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl ether, washed with water, 1 N hydrochloric acid, water, and brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give the product. washed with water, 1 N hydrochloric acid, water, and brine dried over anhydrous Na2SO4 concentrated en vaccuo The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) to give the product