DI-TERT-BUTYL IMINODIACETATE

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

Procedure: A solution of 11.6 g of oxalyl chloride in 25 ml of methylene chloride is added dropwise, in the course of 15 minutes, to a mixture, cooled to -25°, of 20 g of dimethylforinaniide and 115 ml of methylene chloride. The white suspension is stirred for a further 20 minutes at -25°, and a solution of 28.5 g of the dicyclohexylammonium salt of (2R,3R,)-2,3-epoxybutyric acid in 115 ml of methylene chloride is then added in the course of 10 minutes. The reaction mixture is stirred for a further 20 minutes at the same temperature, and a solution of 17.87 g of di-tert-butyl iminodiacetate in 90 ml of methylene chloride and 9.22 ml of N-methylmorpholine are then added dropwise simultaneously in the course of 15 minutes. The cooling bath is removed and the reaction mixture is stirred for 3 hours at room temperature. The white suspension is then filtered through a sintered glass suction filer, the residue is washed with methylene chloride, and the filtrate is diluted with methylene chloride and washed successively with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate solution and water. The aqueous phases are subsequently extracted twice with methylene chloride, and the combined organic phases are dried and evaporated under a water pump vacuum. The yellow-brown crude product is purified by flash chromatography over silica gel (Merck 9385) using a 9:1 mixture of methylene chloride and ethyl acetate as the mobile phase. (2R,3R)-N,N-Bis-(tert-butoxy-carbonylmethyl)-2,3-epoxybutyramide is obtained in the form of a pale yellow oil, [α]D =+52° (c=1.250% in chloroform). The reaction mixture is stirred for a further 20 minutes at the same temperature The cooling bath is removed the reaction mixture is stirred for 3 hours at room temperature The white suspension is then filtered through a sintered glass suction filer the residue is washed with methylene chloride the filtrate is diluted with methylene chloride washed successively with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate solution and water The aqueous phases are subsequently extracted twice with methylene chloride the combined organic phases are dried evaporated under a water pump vacuum The yellow-brown crude product is purified by flash chromatography over silica gel (Merck 9385) a 9:1 mixture of methylene chloride and ethyl acetate as the mobile phase

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

Procedure: To a solution of Example 5 (500 mg, 2.84 mmol) in dichloromethane (10 mL) was added 1,3-diisopropylcarbodiimide (0.44 mL, 2.84 mmol), 1-hydroxybenzotriazole hydrate (115 mg, 0.85 mmol), and di-t-butyl iminodiacetate (1.04 g, 4.26 mmol). The mixture was stirred at room temperature for about 24 hours, quenched with water, and extracted with diethyl ether. The combined organic extracts were washed with brine and saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (1:1) as the mobile phase to provide the desired product. MS (ESI): m/z 402 (M−H)−. quenched with water extracted with diethyl ether The combined organic extracts were washed with brine and saturated aqueous sodium bicarbonate dried (Na2SO4) filtered concentrated under vacuum The residue was purified by flash column chromatography on silica gel

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

Procedure: To a solution of 4-iodo-2,6-bisbromomethylpyridine (0.59 g, 1.5 mmol) and di-t-butyl iminodiacetate (0.74 g, 3.0 mmol) in 40 mL of dry acetonitrile was added 1.59 g of sodium carbonate (15 mmol) and the mixture was stirred for 24 h at room temperature. Filtration and evaporation of the filtrate left a yellow oil. The oil was taken into 20 mL of chloroform, washed twice with 10 mL of water and dried with Na2SO4. Evaporation gave a yellowish oil which was purified by chromatographing on silica with toluene-ethanol (10:1). Filtration and evaporation of the filtrate left a yellow oil washed twice with 10 mL of water dried with Na2SO4 Evaporation gave a yellowish oil which was purified by chromatographing on silica with toluene-ethanol (10:1)

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

Procedure: 4,4'-Bis(chloromethyl)-2,2'-bipyrimidine (18.0 mg, 0.0793 mmoles), di-t-butyl iminodiacetate (76.3 mg, 0.31 mmoles), sodium carbonate (210 mg) and acetonitrile (3 ml) were refluxed overnight. The mixture was filtered, the solvent was evaporated and the product was purified by flash chromatography (silica, 0-5% methanol/chloroform). The mixture was filtered the solvent was evaporated the product was purified by flash chromatography (silica, 0-5% methanol/chloroform)

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

Procedure: To a stirred solution of 6-(benzyloxy)-6-oxohexanoic acid (1.5 g, 6.35 mmol) in DMF (50 mL) at room temperature was added DIPEA (2.218 mL, 12.70 mmol), HOBt (1.945 g, 12.7 mmol), EDC (2.434 g, 12.7 mmol) and di-tert-butyl 2,2′-iminodiacetate (2.34 g, 9.52 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (80 g), eluting with 0-40% EtOAc in hexane, to give the title compound. LC-MS Method A: m/e=464.04 [M+1]; Rt=2.47 min. 1H NMR (CDCl3) δ 7.32 (m, 5H), 5.07 (s, 2H), 4.02 (s, 2H), 3.96 (s, 2H), 2.35 (s, 2H), 2.26 (s, 2H), 1.66 (s, 4H), 1.42-1.44 (bs, 18H). extracted with CH2Cl2 (2×30 mL) The combined organic phase was washed with brine dried over Na2SO4 concentrated The residue was purified by flash chromatography on silica gel (80 g) eluting with 0-40% EtOAc in hexane

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

Procedure: Compound 14 (0.88 g, 3.59 mmol), succinic anhydride (0.377 g, 3.77 mmol), ethyldiisopropylamine (625 μL, 3.59 mmol) and 4-di(methylamino)pyridine (44 mg, 0.359 mmol) were dissolved in CHCl3 (15 mL) and stirred for 48 h. The mixture was diluted with dichloromethane (140 mL) and the organic layer was washed with H2O (2×75 mL) and saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (80% EtOAc in hexanes) to give the compound 15 (0.9 g, 72.6%). 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.47 (s, 9H), 2.62 (t, J=5.8, 2H), 2.69 (t, J=5.8, 2H), 4.02 (s, 2H), 4.06 (s, 2H). ESI-MS calculated for C16H27NO7, 345.59 found 368.1 (M+Na). the organic layer was washed with H2O (2×75 mL) and saturated aqueous NaCl dried over Na2SO4 concentrated under reduced pressure The crude material was purified by silica gel chromatography (80% EtOAc in hexanes)

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

Procedure: To a solution of t-butylglycine (1.40 g, 10.67 mmol) in acetonitrile (20 mL) cooled to 0° C. was added ethyldisopropylamine (1.86 mL, 10.67 mmol) and t-butyl bromoacetate (1.57 mL, 10.67 mmol). The resulting solution was stirred for 24 h at room temperature. The mixture was concentrated to dryness in vacuo, water was added and the solution was extracted with dichloromethane (3×70 mL). The combined organic phases were washed with brine (70 mL), dried over Na2SO4 and concentrated to dryness in vacuo. The crude material was purified by silica gel chromatography (20-80% EtOAc in hexanes) to give the compound 14 (0.88 g, 33.6%). 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 18H), 3.30 (s, 4H). The mixture was concentrated to dryness in vacuo, water was added the solution was extracted with dichloromethane (3×70 mL) The combined organic phases were washed with brine (70 mL) dried over Na2SO4 concentrated to dryness in vacuo The crude material was purified by silica gel chromatography (20-80% EtOAc in hexanes)

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

Procedure: A solution of 11.6 g of oxalyl chloride in 25 ml of methylene chloride is added dropwise, in the course of 15 minutes, to a mixture, cooled to -25°, of 20 g of dimethylforinaniide and 115 ml of methylene chloride. The white suspension is stirred for a further 20 minutes at -25°, and a solution of 28.5 g of the dicyclohexylammonium salt of (2R,3R,)-2,3-epoxybutyric acid in 115 ml of methylene chloride is then added in the course of 10 minutes. The reaction mixture is stirred for a further 20 minutes at the same temperature, and a solution of 17.87 g of di-tert-butyl iminodiacetate in 90 ml of methylene chloride and 9.22 ml of N-methylmorpholine are then added dropwise simultaneously in the course of 15 minutes. The cooling bath is removed and the reaction mixture is stirred for 3 hours at room temperature. The white suspension is then filtered through a sintered glass suction filer, the residue is washed with methylene chloride, and the filtrate is diluted with methylene chloride and washed successively with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate solution and water. The aqueous phases are subsequently extracted twice with methylene chloride, and the combined organic phases are dried and evaporated under a water pump vacuum. The yellow-brown crude product is purified by flash chromatography over silica gel (Merck 9385) using a 9:1 mixture of methylene chloride and ethyl acetate as the mobile phase. (2R,3R)-N,N-Bis-(tert-butoxy-carbonylmethyl)-2,3-epoxybutyramide is obtained in the form of a pale yellow oil, [α]D =+52° (c=1.250% in chloroform). The reaction mixture is stirred for a further 20 minutes at the same temperature The cooling bath is removed the reaction mixture is stirred for 3 hours at room temperature The white suspension is then filtered through a sintered glass suction filer the residue is washed with methylene chloride the filtrate is diluted with methylene chloride washed successively with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate solution and water The aqueous phases are subsequently extracted twice with methylene chloride the combined organic phases are dried evaporated under a water pump vacuum The yellow-brown crude product is purified by flash chromatography over silica gel (Merck 9385) a 9:1 mixture of methylene chloride and ethyl acetate as the mobile phase