2-(hydroxymethyl)propane-1,3-diol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-Hydroxymethyl-1,3-propanediol (9.0 g, 61.6 mmol), 2,2-dimethoxypropane (11.7 ml, 95.2 mmol) 4-toluenesulphonic acid monohydrate (0.49 g, 2.58 mmol) and tetrahydrofuran (450 ml) was stirred at 20° C. for 1 hour. Triethylamine (5 ml) was then added and the solvent removed under reduced pressure. Chromatography on silica gel (eluted with chloroform ethanol, 10.1) afforded the title compound (9.62 g, 78%) as a colourless oil. 1R: υmax (film) 3431, 2993, 2943, 2874, 1482, 1456, 1373 cm-1. 1H NMR: δH [(CD3)2SO] 1.30(6H, s, 2×CH3), 1.69(1H,m,CH), 3.38(2H,dd, J=5.2, 6.6 Hz, CH2OH), 3.61(2H,dd, J=11.8, 7.1 Hz, 2×H(ax)), 3.82 (2H, dd, J=11.8, 4.4 Hz, 2×H(eq)), 4.53(1H, t, J=5.2 Hz, D2O exchangable, OH). Found: C, 56.73; H, 9.80%. C7H14O3.0.01H2O requires: C, 56.80; H, 9.69%. the solvent removed under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of methylene chloride (150 ml) and a 1:1 mixture of anhydrous nitric acid and 30% fuming sulfuric acid (40 ml) carefully stirred at 10° to 15%C. is added portionwise 2-hydroxymethyl-1,3-propanediol (7.5 g) while measuring the redox potential of the solution and maintaining it between -0.07 and 0.20 volts. This is conveniently done with an Ingold Redox probe charged with the mixed acid. When the addition is complete the phases are separated, the organic phase washed with water, aqueous sodium bicarbonate and aqueous urea, dried over sodium sulfate and/or molecular sieves and the solvent evaporated to give the title product (15 g) m.p. 11°-12° C.,D 1.53,nD29.5 1.4746. maintaining it between -0.07 and 0.20 volts charged with the mixed acid When the addition are separated the organic phase washed with water, aqueous sodium bicarbonate and aqueous urea dried over sodium sulfate and/or molecular sieves the solvent evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(hydroxymethyl)-1,3-propanediol (9.4 mmol) in dichloromethane (20 mL) and pyridine (7.5 mL) at 0° C. was added methyl chloroformate (9.4 mmol) slowly. The resulting solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure and chromatographed by eluting with methanol-dichloromethane (1:4) to give 650 mg of 2-(methoxycarbonyloxymethyl)-1,3-propanediol. The reaction was concentrated under reduced pressure chromatographed by eluting with methanol-dichloromethane (1:4)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (60% dispersion in oil) (2.93 g, 73.2 mmol) was added to an ice-cooled solution of 2-hydroxymethyl-propane-1,3-diol (M. R. Harnden et al. J. Med. Chem. 1990, 33, 187) (3.53 g, 33.3 mmol) in DMF (100 ml) and the mixture was stirred at room temperature for 40 min. The reaction mixture was cooled with ice and iodomethane (4.56 ml, 73.2 mmol) was added, the stirring was continued allowing the mixture to reach room temperature over 24 h. The mixture was poured into ethyl acetate (300 ml) and washed with brine (150 ml). The organic phase was dried (MgSO4), and the solvent was evaporated. The crude product was purified by flash column chromatography (silica, ethyl acetate) to afford colourless oil. 1H NMR (300 MHz, CDCl3) 3.72 (2H, d), 3.47 (2H, d), 3.45 (2H, d), 3.32 (6H, s), 2.07(1H, m). was added to reach room temperature over 24 h washed with brine (150 ml) The organic phase was dried (MgSO4) the solvent was evaporated The crude product was purified by flash column chromatography (silica, ethyl acetate) to afford colourless oil

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (60% dispersion in oil) (2.93 g, 73.2 mmol) was added to an ice-cooled solution of 2-hydroxymethyl-propane-1,3-diol (M. R. Harnden et al. J. Med. Chem. 1990, 33, 187) (3.53 g, 33.3 mmol) in DMF (100 ml) and the mixture was stirred at room temperature for 40 min. The reaction mixture was cooled with ice and iodomethane (4.56 ml, 73.2 mmol) was added, the stirring was continued allowing the mixture to reach room temperature over 24 h. The mixture was poured into ethyl acetate (300 ml) and washed with brine (150 ml). The organic phase was dried (MgSO4), and the solvent was evaporated. The crude product was purified by flash column chromatography (silica, ethyl acetate) to afford colourless oil. 1H NMR (300 MHz, CDCl3) 3.72 (2H, d), 3.47 (2H, d), 3.45 (2H, d), 3.32 (6H, s), 2.07(1H, m). was added to reach room temperature over 24 h washed with brine (150 ml) The organic phase was dried (MgSO4) the solvent was evaporated The crude product was purified by flash column chromatography (silica, ethyl acetate) to afford colourless oil

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(hydroxymethyl)-1,3-propanediol (1 g, 9.4 mmol) in pyridine (7.5 mL) at 0° C. was added acetic anhydride (0.89 mL, 9.4 mmol) slowly. The resulting solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure and chromatographed by eluting with methanol-dichloromethane (1:9) to give 510 mg of pure 2-acetoxymethyl-1,3-propanediol. The reaction was concentrated under reduced pressure chromatographed by eluting with methanol-dichloromethane (1:9)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(hydroxymethyl)-1,3-propanediol (1 g, 9.4 mmol) in pyridine (7.5 mL) at 0° C. was added acetic anhydride (0.89 mL, 9.4 mmol) slowly. The resulting solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated under reduced pressure and chromatographed by eluting with methanol-dichloromethane (1:9) to give 510 mg of pure 2-acetoxymethyl-1,3-propanediol. The reaction was concentrated under reduced pressure chromatographed by eluting with methanol-dichloromethane (1:9)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Hydroxybenzophenone is treated with equimolar quantity of sodium hydride in dry dimethylformamide at 0° C. under an inert atmosphere. After stirring at ambient temperature for 2 hours, a bright yellow clear solution is obtained. To this solution is added equimolar quantity of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (its synthesis in two steps from commercially available 2-hydroxymethyl-1,3-propanediol is described in European Patent EP2103611). After stirring at ambient temperature for 16 hours, the reaction mixture is diluted with water and extracted with dichloromethane. The organic phase is evaporated to dryness and the crude product is purified by column chromatography. This provide the intermediate {4-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]phenyl}(phenyl)methanone. This intermediate is then dissolved in acetone, excess of 1M hydrochloric acid is added and the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is evaporated to dryness under reduced pressure, and the residue is purified by column chromatography to provide the desired {4-[3-hydroxy-2-(hydroxymethyl)propoxy]phenyl}(phenyl)methanone. a bright yellow clear solution is obtained After stirring at ambient temperature for 16 hours extracted with dichloromethane The organic phase is evaporated to dryness the crude product is purified by column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: NaH (15 mg, 0.6 mmol) was added to 2-(hydroxymethyl)-1,3-propanediol in THF (5 mL). The mixture was allowed to stir at 23° under Ar for 10 min and was then cooled to −78°. The product of Example 48 (224 mg, 0.5 mmol) in THF (5 mL) was added at −78° and the mixture allowed to warm to 23° and stir for 2 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 70% EtOAc/CH2Cl2 the title compound as a white-amorphous solid. mp 77-81°, LC MS m/z=472 (MH+) Retention time=1.79 min. was then cooled to −78° to warm to 23° stir for 2 h The solvents were removed in vacuo the residue was partitioned between EtOAc and H2O The organic phase was washed with H2O dried over anhyd Na2SO4 filtered evaporated