[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol

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

Procedure: To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 33.5 g, 0.145 mol) and ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-l-ol (15 g, 0.113 mol) in anhydrous dichloromethane (750 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC, 23 g, 0.12 mol) and N,N-dimethylaminopyridine (DMAP, 7.5 g, 61 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and solvent evaporated under reduced temperature. The product was purified by column chromatography on silica gel eluting with EtOAc:hexane (2:8) to give the title compound (35.8 g, 92% yield) as a white solid. Mp 79-80° C. 1H NMR (CDCl3) δ 7.76 (d, J=9.1 Hz, 2H), 7.46 (dd, J=8.7, 1.8 Hz, 1H), 7.19 (m, 2H), 7.0 (s, 1H), 4.28 (m, 1H), 4.18 (m, 2H), 4.0 (m, 2H), 3.94 (s, 3H), 3.68 (m, 1H), 1.65 (d, J=7.1 Hz, 3H), 1.41 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 135.3, 133.7, 129.2, 128.9, 127.1, 126.1, 126.0, 119.0, 109.6, 105.5, 73.4, 66.1, 64.4, 55.2, 45.2, 26.5, 25.3, 18.4; LRMS (APIMS) m/z 345 (MH)+. quenched with water The organic layer was washed with brine dried over sodium sulfate filtered solvent evaporated under reduced temperature The product was purified by column chromatography on silica gel eluting with EtOAc:hexane (2:8)

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

Procedure: To a solution of ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-1-ol (9 g, 68.6 mmol) in anhydrous dichloromethane (40 mL) were added triethylamine (11.2 mL), tert-butylchlorodiphenylsilane (19.8 g, 372 mmol), and N,N-dimethylaminopyridine (DMAP, 418 mg, 3.4 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. It was then diluted with additional dichloromethane and the reaction mixture was washed with water, brine, dried over sodium sulfate, filtered and evaporated to give the title compound (27 g) which was used in the next step without further purification. the reaction mixture was washed with water, brine dried over sodium sulfate filtered evaporated

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

Procedure: (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (11 grams), powdered potassium hydroxide (20 grams) and hexadecyl bromide (27.96 grams) in toluene (150 ml) were stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 40 ml. The reaction mixture was cooled to room temperature; water was added (100 ml) and the resulting mixture was extracted with dichloromethane (3×75 ml). The combined organic phase was washed with water (50 ml) and the solvent removed under reduced pressure. The residue was dissolved in 200 ml mixture of 90:10:5 methanol:water:concentrated hydrochloric acid (v/v) and the resulting solution was refluxed for 2 hours, followed by cooling to room temperature and addition of water (100 ml). The product was extracted with dichloromethane (3×100 ml), and the organic phase was washed consecutively with water (100 ml). saturated aqueous solution of sodxium carbonate (100 ml) and again with water (100 ml). The solvent was removed under reduced pressure and the product was crystallized from hexane (200 ml) to give 21.69 grams (yield 82%) of pure 1-hexadecyl-glycerol. upon drying in a desiccator under reduced pressure. refluxed for 6 hours while removing the water formed by azeotropic distillation the resulting mixture was extracted with dichloromethane (3×75 ml) The combined organic phase was washed with water (50 ml) the solvent removed under reduced pressure The residue was dissolved in 200 ml mixture of 90:10:5 methanol water:concentrated hydrochloric acid (v/v) and the resulting solution was refluxed for 2 hours by cooling to room temperature addition of water (100 ml) The product was extracted with dichloromethane (3×100 ml) the organic phase was washed consecutively with water (100 ml) The solvent was removed under reduced pressure the product was crystallized from hexane (200 ml)

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

Procedure: tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.15 g, 0.24 mmol, see Example 9), Cu(I)I (0.046 g, 0.24 mmol), 1,10-phenanthroline (0.043 g, 0.24 mmol), (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (0.95 g, 7.2 mmol) and KF on Al2O3 (40%; 0.24 g, 1.68 mmol) in toluene (4 mL) was stirred at 110° C. for 60 hours. Ethyl acetate (10 mL) was then added, and the reaction mixture was filtered through a pad of celite. The reaction was then concentrated to dryness, and the residue was purified by column chromatography (hexane:ethyl acetate=1:1) to give (R)-tert-butyl 4-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.14 g, 93%) as a solid. MS APCI (+) m/z 630.2 detected. the reaction mixture was filtered through a pad of celite The reaction was then concentrated to dryness the residue was purified by column chromatography (hexane:ethyl acetate=1:1)

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

Procedure: To a solution of 3-chloro-4-hydroxybenzaldehyde (4.21 g, 27 mmol) in degassed toluene (100 mL) is added ((4R)-2,2-dimethyl-[1,3]-dioxolan-4-yl)-methanol (5.35 g, 40.5 mmol), 1,1′-(azodicarbonyl)dipiperidide (13.63 g, 54 mmol) followed by tributylphosphine (10.93 g, 54 mmol). The mixture becomes slightly warm and a precipitate forms. The reaction mixture is diluted with degassed toluene (500 mL) and is stirred at it for 2 h, then at 60° C. for further 18 h before it is washed with 1 N aq. NaOH (3×150 mL) and water (150 mL). The organic phase is dried over MgSO4, filtered and concentrated to leave a dark brown oil which is chromatographed on silica gel eluting with hexane/EA 4:1 to give the title compound (4.30 g) as yellow oil. 1H NMR (CDC3): δ 9.82 (s, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.74 (dd, J=1.8, 8.2 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 4.56-4.43 (m, 1H), 4.23-4.17 (m, 2H), 4.14-4.08 (m, 1H), 4.06-4.00 (m, 1H), 1.47 (s, 3H), 1.41 (s, 3H). The mixture becomes slightly warm at 60° C. for further 18 h before it is washed with 1 N aq. NaOH (3×150 mL) and water (150 mL) The organic phase is dried over MgSO4 filtered concentrated to leave a dark brown oil which is chromatographed on silica gel eluting with hexane/EA 4:1

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

Procedure: To a solution of 3-chloro-4-hydroxybenzaldehyde (4.21 g, 27 mmol) in degassed toluene (100 mL) is added ((4R)-2,2-dimethyl-[1,3]-dioxolan-4-yl)-methanol (5.35 g, 40.5 mmol), 1,1′-(azodicarbonyl)dipiperidide (13.63 g, 54 mmol) followed by tributylphosphine (10.93 g, 54 mmol). The mixture becomes slightly warm and a precipitate forms. The reaction mixture is diluted with degassed toluene (500 mL) and is stirred at it for 2 h, then at 60° C. for further 18 h before it is washed with 1 N aq. NaOH (3×150 mL) and water (150 mL). The organic phase is dried over MgSO4, filtered and concentrated to leave a dark brown oil which is chromatographed on silica gel eluting with hexane/EA 4:1 to give the title compound (4.30 g) as yellow oil. 1H NMR (CDC3): δ 9.82 (s, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.74 (dd, J=1.8, 8.2 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 4.56-4.43 (m, 1H), 4.23-4.17 (m, 2H), 4.14-4.08 (m, 1H), 4.06-4.00 (m, 1H), 1.47 (s, 3H), 1.41 (s, 3H). The mixture becomes slightly warm at 60° C. for further 18 h before it is washed with 1 N aq. NaOH (3×150 mL) and water (150 mL) The organic phase is dried over MgSO4 filtered concentrated to leave a dark brown oil which is chromatographed on silica gel eluting with hexane/EA 4:1

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

Procedure: To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (2.89 g, 17.9 mmol) in THF (80 mL), (R)-(2,2-dimethyl-[1,3]dioxolan-4-yl)methanol (2.84 g, 21.5 mmol) followed by triphenylphosphine (5.81 g, 21.5 mmol) is added. The mixture is cooled with an ice-bath before DEAD (9.36 g, 21.5 mmol) is added dropwise. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by CC on silica gel eluting with heptane:EA 85:15 to give (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-benzonitrile (4.45 g) as a pale yellow oil; LC-MS**: tR=0.75 min, [M+1]+=not detected; 1H NMR (CDCl3): δ1.25 (t, J=7.5 Hz, 3H), 1.44 (s, 3H), 1.49 (s, 3H), 2.34 (s, 3H), 2.65-2.77 (m, 2H), 3.80-3.90 (m, 2H), 3.94-4.00 (m, 1H), 4.21 (t, J=7.3 Hz, 1H), 4.52 (quint, J=5.8 Hz, 1H), 7.35 (s, 1H), 7.38 (s, 1H). is added is added dropwise the solvent is removed in vacuo the residue is purified by CC on silica gel eluting with heptane:EA 85:15

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

Procedure: To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (2.89 g, 17.9 mmol) in THF (80 mL), (R)-(2,2-dimethyl-[1,3]dioxolan-4-yl)methanol (2.84 g, 21.5 mmol) followed by triphenylphosphine (5.81 g, 21.5 mmol) is added. The mixture is cooled with an ice-bath before DEAD (9.36 g, 21.5 mmol) is added dropwise. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by CC on silica gel eluting with heptane:EA 85:15 to give (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-ethyl-5-methyl-benzonitrile (4.45 g) as a pale yellow oil; LC-MS**: tR=0.75 min, [M+1]+=not detected; 1H NMR (CDCl3): δ1.25 (t, J=7.5 Hz, 3H), 1.44 (s, 3H), 1.49 (s, 3H), 2.34 (s, 3H), 2.65-2.77 (m, 2H), 3.80-3.90 (m, 2H), 3.94-4.00 (m, 1H), 4.21 (t, J=7.3 Hz, 1H), 4.52 (quint, J=5.8 Hz, 1H), 7.35 (s, 1H), 7.38 (s, 1H). is added is added dropwise the solvent is removed in vacuo the residue is purified by CC on silica gel eluting with heptane:EA 85:15

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

Procedure: A mixture of (R)-2,2-dimethyl-1,3-dioxolane-4-methanol (7.3 g, 0.05 mol), N-hydroxyphthalimide (8.15 g, 0.05 mol) and triphenylphosphine (13.11 g, 0.05 mol) in tetrahydrofuran (200 ml) was cooled to 0° C. and stirred during the addition of diethyl azodicarboxylate (9.57 g, 0.066 mol). The dark red solution was stirred at 25° C. for 18 h when the colour had turned to pale yellow, and the solution was evaporated to dryness. The residue was extracted once with ether (200 ml) and the ether removed under reduced pressure. The residue was chromatographed in chloroform-hexane 10:1 affording (S)-N-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)phthalimide (10.5 g, 69%) as a white solid; m.p. 99°-100° C., [α]D25 -14.6° (0.4 in MeOH); υmax (KBr) [α]D25 1790, 1730 and 1610 cm-1 ; δH (CDCl3) 1.35(3H,S,CH3), 1.4 (3H,S,CH3), 3.99(1H,q,J5.5,8.8 Hz,CH2ON/CH2OCMe2), 4.17(2H,m,1H of CH2ON+1H of CH2OCMe2), 4.32(1H,q,J5.7,10.1 Hz,CH2ON/CH2OCMe2), 4.50(1H,m,CH) and 7.75-7.87(4H,m,aromatic). Found: C, 60.53; H, 5.46; N, 5.03%. C14H15NO5 requires C, 60.64; H, 5.45; N, 5.05%. was evaporated to dryness The residue was extracted once with ether (200 ml) the ether removed under reduced pressure The residue was chromatographed in chloroform-hexane 10:1 affording (S)-N-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)phthalimide (10.5 g, 69%) as a white solid

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and (R)- or (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3-5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hrs. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 h. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 h at 3-5° C. The white solid was filtered, washed with a small amount of cold EtOH and dried in vacuum oven at 40° C. to give (S)- or (R)-2-(2,2-Dimethyl-[1,3]dioxolan-4ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1). A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel the inner temperature below 15° C The reaction mixture was warmed to ambient temperature The tetrahydrofuran was evaporated under reduced pressure To the remaining orange solid was added dichloromethane (0.5 L) the mixture was stirred for 1 h The white solid (Ph3PO) was filtered washed with dichloromethane (0.1 L) The solvent was removed ethanol (0.5 L) was added to the resulting solid The mixture was stirred for 2 h at 3-5° C The white solid was filtered washed with a small amount of cold EtOH dried in vacuum oven at 40° C.

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and (R)- or (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3-5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hrs. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 h. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 h at 3-5° C. The white solid was filtered, washed with a small amount of cold EtOH and dried in vacuum oven at 40° C. to give (S)- or (R)-2-(2,2-Dimethyl-[1,3]dioxolan-4ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1). A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel the inner temperature below 15° C The reaction mixture was warmed to ambient temperature The tetrahydrofuran was evaporated under reduced pressure To the remaining orange solid was added dichloromethane (0.5 L) the mixture was stirred for 1 h The white solid (Ph3PO) was filtered washed with dichloromethane (0.1 L) The solvent was removed ethanol (0.5 L) was added to the resulting solid The mixture was stirred for 2 h at 3-5° C The white solid was filtered washed with a small amount of cold EtOH dried in vacuum oven at 40° C.

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

Procedure: To a stirring suspension of 5,6-O-isopropylidene-L-gulono-1,4-lactone (15.16 g, 69.5 mmol) in water (0.3 L) was added solid sodium periodate in small portions at 3-5° C. The pH of the mixture was adjusted to 5.5 with 1N aqueous sodium hydroxide. The suspension was stirred for 2 hrs at ambient temperature, then saturated with sodium chloride (20.0 g) and filtered. To the filtrate, at 3-5° C., was added sodium borohydride (10.5 g, 0.278 mol) in small portions. The reaction mixture was stirred for 18 h at ambient temperature. Acetone (100 mL) was added to destroy the excess of sodium borohydride, and the stirring was continued for 30 minutes. The acetone was removed under reduced pressure and the aqueous residue was extracted with dichloromethane (3×300 mL) and EtOAc (3×300 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to give (R)-(+)-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol (5.07 g, 55.7%) as a colorless clear liquid: MS(APCI+)=132.9 (M++1). saturated with sodium chloride (20.0 g) and filtered The reaction mixture was stirred for 18 h at ambient temperature to destroy the excess of sodium borohydride the stirring was continued for 30 minutes The acetone was removed under reduced pressure the aqueous residue was extracted with dichloromethane (3×300 mL) and EtOAc (3×300 mL) The combined organic layers were dried over magnesium sulfate filtered evaporated