(2R)-1-methoxypropan-2-ol

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

Procedure: Methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate (1.0 eq.), (R)-1-methoxy-2-propanol (1.25 eq.) and triphenylphosphine (1.25 eq.) were suspended in toluene (10 vol). Diisopropyl azodicarboxylate (1.25 eq.) was added at a batch temperature of between 0 and 5° C. over ˜2 h. The mixture was allowed to warm to room temperature and was stirred for further 30 min. at this temperature. The resulting suspension was filtered to remove the bulk of the triphenylphosphine oxide formed and the filter cake was washed with toluene (1.5 vol). To the combined toluene fractions containing the resulting methyl 3-[(1S)-2-methoxy-1-methylethoxy]-5-[(phenylcarbonyl)oxy]benzoate was added sodium methylate (0.8 eq.) at a batch temperature of between 20 and 30° C. and the mixture was stirred to 1 h. The solution of the resulting methyl 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]-benzoate was then extracted twice with KOH 0.25 M (3.5 vol each) at a batch temperature of between 0 and 5° C. KOH was then added (1 eq.) to hydrolyse the ester moiety and the batch was stirred for 1 h at a temperature of between 20 and 30° C. The pH of the aqueous phase is then adjusted to 1.5 using conc. hydrochloric at a batch temperature of <30° C. Crude 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid was subsequently extracted into MTBE (2×3 vol) before activated charcoal was added. The batch was stirred for 10 minutes and then filtered. The batch was reduced to 3 pot volumes by distillation at a batch temperature of <45° C. Toluene (4 vol) and heptane (1 vol) were added and vacuum distillation was continued at a batch temperature of <50° C. until no further MTBE was collected. The batch was cooled to a temperature of <40° C., seeded and further cooled to a batch temperature of between 28 and 32° C. The resulting suspension was stirred for 1 h at this temperature before being further cooled to 5 to 10° C. After 2 h stirring at 5 to 10° C. the batch was filtered and washed with cold toluene (1 vol.). Drying at <60° C. furnished 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid in >99% purity as colourless solid with a melting point of 95° C. in a typical yield between 65 and 70% from methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate. The resulting suspension was filtered to remove the bulk of the triphenylphosphine oxide formed the filter cake was washed with toluene (1.5 vol) To the combined toluene fractions containing the resulting methyl 3-[(1S)-2-methoxy-1-methylethoxy]-5-[(phenylcarbonyl)oxy]benzoate the mixture was stirred to 1 h The solution of the resulting methyl 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]-benzoate was then extracted twice with KOH 0.25 M (3.5 vol each) at a batch temperature of between 0 and 5° C KOH was then added (1 eq.) the batch was stirred for 1 h at a temperature of between 20 and 30° C is then adjusted to 1.5 using conc. hydrochloric at a batch temperature of <30° C Crude 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid was subsequently extracted into MTBE (2×3 vol) was added The batch was stirred for 10 minutes filtered The batch was reduced to 3 pot volumes by distillation at a batch temperature of <45° C Toluene (4 vol) and heptane (1 vol) were added vacuum distillation was continued at a batch temperature of <50° C. until no further MTBE was collected The batch was cooled to a temperature of <40° C. further cooled to a batch temperature of between 28 and 32° C The resulting suspension was stirred for 1 h at this temperature before being further cooled to 5 to 10° C After 2 h stirring at 5 to 10° C. the batch was filtered washed with cold toluene (1 vol.) Drying at <60° C.

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3 eq) and toluene (5 vols) under a nitrogen atmosphere and the reaction mixture agitated to form an oily slurry. The slurry was cooled to −5° C., then (2R)-1-methoxypropan-2-ol (1.0 eq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a line wash followed by triethylamine (1.5 eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature<8° C. Further toluene (2.5 vols) was added as a line wash and the reaction mixture held at −5° C. to 5° C. for 4.5 hours. N,N-dimethyl-1,3-propane-diamine, (0.3 eq) was added over 10 minutes at −5° C. The reaction mixture was agitated at −5° C. to 5° C. for 30 minutes, then 2N hydrochloric acid (0.55 eq) and 70 ml water were added. The reaction mixture was agitated for 30 minutes at 22° C. and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) then the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to an oil to give the title compound as a dry light brown oil. Yield corrected for assay 93-97%. 1H NMR δ (400 MHz CDCl3): 7.78-7.75 (d, 2H), 7.45-7.43 (d, 2H), 4.66-4.62 (m, 1H), 3.35-3.26 (m, 2H), 3.16 (s, 3H), 2.4 (s, 3H), 1.13-1.11 (d, 3H). To a flask fitted with overhead stirrer, condenser to form an oily slurry wash was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature<8° C wash The reaction mixture was agitated at −5° C. to 5° C. for 30 minutes The reaction mixture was agitated for 30 minutes at 22° C. the aqueous layer was separated off The mixture was washed twice more with water (10 vols each wash) then the toluene layer was distilled to an oil on the rotary evaporator Toluene (20 vols) was added to the oil the solution evaporated to an oil

Conditions: temp:8.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask was added under a nitrogen atmosphere trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3 eq) and toluene (5 vols) and the reaction mixture agitated to form an oily slurry. The slurry was cooled to −5° C. (2R)-1-Methoxypropan-2-ol (1.0 eq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a wash followed by triethylamine (1.5 eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature<8° C. Further toluene (2.5 vols) was added as a wash and the reaction mixture held at −5° C. to 5° C. for 4.5 hours. N,N-Dimethyl-1,3-propane-diamine (0.3 eq) was added over 10 minutes at −5° C. The mixture was agitated at −5° C. to 5° C. for 30 minutes. Then 2N hydrochloric acid (0.55 eq) and 70 ml water were added. The mixture was agitated for 30 minutes at 22° C. and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) and after separation of the aqueous wash, the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to give the title compound as a dry light brown oil. Yield (corrected for assay) 93-97%. to form an oily slurry was added drop-wise over 30 minutes was added drop-wise via addition funnel over 30 minutes a wash The mixture was agitated at −5° C. to 5° C. for 30 minutes The mixture was agitated for 30 minutes at 22° C. the aqueous layer was separated off The mixture was washed twice more with water (10 vols each wash) and after separation of the aqueous wash the toluene layer was distilled to an oil on the rotary evaporator Toluene (20 vols) was added to the oil the solution evaporated

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

Procedure: Magnesium perchlorate (2.73 g, 12.24 mmol) was added in one portion to (S)-methyl oxirane-2-carboxylate (CAS no. 118712-39-3) (5 g, 48.98 mmol) and (R)-1-methoxypropan-2-ol (CAS no. 4984-22-9) (4.41 g, 48.98 mmol) at room temperature. The resulting suspension was stirred at 50° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL), dried (MgSO4) and evaporated. This was not isolated and used crude in next step. at room temperature washed with water (20 mL) dried (MgSO4) evaporated This was not isolated

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

Procedure: Pyridin-4-ol (10 g, 105.15 mmol), (R)-1-methoxypropan-2-ol (9.48 g, 105.15 mmol) and triphenylphosphine (30.3 g, 115.67 mmol) were added to THF (250 mL) and stirred for 10 minutes. To this was slowly added DIAD (22.49 mL, 115.67 mmol) and the reaction was stirred for 1 hour at 25° C. The solvent was evaporated and diethyl ether (100 mL) was added. To this was added a little triphenyl phosphine oxide and the reaction was stirred for 20 minutes to afford a solid, which was discarded. The solvent was evaporated and the pale yellow gum was acidified with 2.0 HCl, extracted with Et2O (1×75 mL) and the aqueous was then basified with solid KOH. This was then extracted with Et2O (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow gum. This was purified by distillation at 0.43 mBar, collecting fractions that distilled at 80° C. to afford the desired material as a colourless oil (15.30 g, 87% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.34 (3H, d), 3.40 (3H, s), 3.50 (1H, dd), 3.58 (1H, dd), 4.68-4.60 (1H, m), 6.82 (2H, d), 8.40 (2H, d); m/z (LC-MS, ESI+), RT=1.28 (M+H 168). the reaction was stirred for 1 hour at 25° C The solvent was evaporated diethyl ether (100 mL) was added To this was added a little triphenyl phosphine oxide the reaction was stirred for 20 minutes to afford a solid, which The solvent was evaporated extracted with Et2O (1×75 mL) This was then extracted with Et2O (3×75 mL) the organic layer was dried over MgSO4 filtered evaporated to afford yellow gum This was purified by distillation at 0.43 mBar collecting fractions that distilled at 80° C.

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

Procedure: Pyridin-4-ol (10 g, 105.15 mmol), (R)-1-methoxypropan-2-ol (9.48 g, 105.15 mmol) and triphenylphosphine (30.3 g, 115.67 mmol) were added to THF (250 mL) and stirred for 10 minutes. To this was slowly added DIAD (22.49 mL, 115.67 mmol) and the reaction was stirred for 1 hour at 25° C. The solvent was evaporated and diethyl ether (100 mL) was added. To this was added a little triphenyl phosphine oxide and the reaction was stirred for 20 minutes to afford a solid, which was discarded. The solvent was evaporated and the pale yellow gum was acidified with 2.0 HCl, extracted with Et2O (1×75 mL) and the aqueous was then basified with solid KOH. This was then extracted with Et2O (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow gum. This was purified by distillation at 0.43 mBar, collecting fractions that distilled at 80° C. to afford the desired material as a colourless oil (15.30 g, 87% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.34 (3H, d), 3.40 (3H, s), 3.50 (1H, dd), 3.58 (1H, dd), 4.68-4.60 (1H, m), 6.82 (2H, d), 8.40 (2H, d); m/z (LC-MS, ESI+), RT=1.28 (M+H 168). the reaction was stirred for 1 hour at 25° C The solvent was evaporated diethyl ether (100 mL) was added To this was added a little triphenyl phosphine oxide the reaction was stirred for 20 minutes to afford a solid, which The solvent was evaporated extracted with Et2O (1×75 mL) This was then extracted with Et2O (3×75 mL) the organic layer was dried over MgSO4 filtered evaporated to afford yellow gum This was purified by distillation at 0.43 mBar collecting fractions that distilled at 80° C.

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

Procedure: To a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7 g of 3 mmol/g loading, 155 mmol) and (R)-(−)-1-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification. cooled in an ice bath filtered washing the residue with THF (500 mL) evaporated

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

Procedure: To a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (77.4 mmol) in THF was added polymer-supported triphenylphosphine (51.7 g of 3 mmol/g loading, 155 mmol) and (R)-(−)-1-methoxy-2-propanol (102 mmol). The stirred solution was blanketed with argon and cooled in an ice bath. A solution of DIAD (116 mmol) was added dropwise by syringe over 10 minutes. The solution was stirred for 20 minutes and filtered, washing the residue with THF (500 mL). The filtrate and washings were combined, and evaporated to give the desired compound which was used without further purification. cooled in an ice bath filtered washing the residue with THF (500 mL) evaporated

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

Procedure: 3-Bromo-5-methoxyphenol (7.60 g, 37.4 mmol) synthesized in Example (78a) was dissolved in toluene (100 mL), and R-(−)-1-methoxy-2-propanol (4.40 mL, 44.9 mmol) and triphenylphosphine (13.8 g, 52.6 mmol) were added, followed by dropwise addition of diethyl azodicarboxylate (2.2 mol/l toluene solution, 24 mL, 52.8 mmol) at 0° C. and stirring at room temperature for 1.5 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, diethyl ether (100 mL) was added, and the deposit was filtered to be removed. The mother liquor was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (9.22 g, yield 89%) as a colorless liquid. The solvent was distilled off under reduced pressure, diethyl ether (100 mL) was added the deposit was filtered to be removed The mother liquor was distilled off under reduced pressure the resulting residue was purified silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%)

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

Procedure: 3-Bromo-5-methoxyphenol (7.60 g, 37.4 mmol) synthesized in Example (1a) was dissolved in toluene (100 mL), and R-(−)-1-methoxy-2-propanol (4.40 mL, 44.9 mmol) and triphenylphosphine (13.8 g, 52.6 mmol) were added, followed by dropwise addition of diethyl azodicarboxylate (2.2 mol/l toluene solution, 24 mL, 52.8 mmol) at 0° C. and stirring at room temperature for 1.5 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, diethyl ether (100 mL) was added, and the deposit was filtered to be removed. The mother liquor was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (9.22 g, yield 89%) as a colorless liquid. The solvent was distilled off under reduced pressure, diethyl ether (100 mL) was added the deposit was filtered to be removed The mother liquor was distilled off under reduced pressure the resulting residue was purified silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%)

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

Procedure: 3-Bromo-5-[4-(methylsulfonyl)phenoxy]phenol (4.86 g, 14.2 mmol) synthesized in Example (1c) was dissolved in toluene (100 mL), and (R)-(−)-1-methoxy-2-propanol (1.77 mL, 18.1 mmol) and triphenylphosphine (4.10 g, 15.6 mmol) were added, followed by cooling to 0° C. Under nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 7.75 mL, 17.1 mmol) was added dropwise over 10 minutes and stirring was carried out at 0° C. for 30 minutes, followed by raising the temperature naturally and stirring at room temperature overnight. Water (100 mL) and ethyl acetate (100 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (5.06 g, yield 86%) as a pale yellow oil. by raising the temperature naturally stirring at room temperature overnight the solution was separated The organic layer was washed with saturated brine subsequently dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the resulting residue was purified silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%)

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

Procedure: 3-Bromo-5-[4-(methylsulfonyl)phenoxy]phenol (4.86 g, 14.2 mmol) synthesized in Example (1c) was dissolved in toluene (100 mL), and (R)-(−)-1-methoxy-2-propanol (1.77 mL, 18.1 mmol) and triphenylphosphine (4.10 g, 15.6 mmol) were added, followed by cooling to 0° C. Under nitrogen atmosphere, diethyl azodicarboxylate (40% toluene solution, 7.75 mL, 17.1 mmol) was added dropwise over 10 minutes and stirring was carried out at 0° C. for 30 minutes, followed by raising the temperature naturally and stirring at room temperature overnight. Water (100 mL) and ethyl acetate (100 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (5.06 g, yield 86%) as a pale yellow oil. by raising the temperature naturally stirring at room temperature overnight the solution was separated The organic layer was washed with saturated brine subsequently dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the resulting residue was purified silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%)