bis(2,5-dioxopyrrolidin-1-yl) carbonate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 2-aminothiazole (10.02 g, 100 mmol) and pyridine (8.3 mL, 103 mmol) in anhydrous acetonitrile (300 mL) was added to a thick suspension of N,N′-disuccinimidyl carbonate (26.13 g, 102 mmol) in acetonitrile (25 mL) with a small acetonitrile rinse. The mixture was stirred thoroughly for another 20 minutes, and then (R)-3-fluoropyrrolidine hydrochloride (13.06 g, 104 mmol) and diisopropylethylamine (70 mL, 402 mmol) were added and the reaction was stirred at room temperature overnight before being concentrated under vacuum. The residue was dissolved into ethyl acetate (100 mL), and then partitioned with hexanes (20 mL) and 3:1 water/brine (20 mL). The aqueous phase was separated and repeatedly back-extracted with 5:1 ethyl acetate/hexanes. The combined organic phases were washed with brine, and the aqueous phase was back-extracted with more 5:1 solution. The combined organic phases were then concentrated. The solids were dissolved into 6:1 dichloromethane/hexanes, mixed with 4:1 water/brine, and filtered through diatomaceous earth with a 6:1 dichloromethane/hexanes rinse. The filtrate was washed with more dilute brine, and the aqueous phase was separated and back-extracted with more 6:1 solution. This wash with dilute brine was repeated two more times. Then the organic phase was dried (sodium sulfate) and concentrated under vacuum to give the title compound. rinse the reaction was stirred at room temperature overnight before being concentrated under vacuum The residue was dissolved into ethyl acetate (100 mL) partitioned with hexanes (20 mL) and 3:1 water/brine (20 mL) The aqueous phase was separated repeatedly back-extracted with 5:1 ethyl acetate/hexanes The combined organic phases were washed with brine the aqueous phase was back-extracted with more 5:1 solution The combined organic phases were then concentrated The solids were dissolved into 6:1 dichloromethane/hexanes mixed with 4:1 water/brine filtered through diatomaceous earth with a 6:1 dichloromethane/hexanes rinse The filtrate was washed with more dilute brine the aqueous phase was separated back-extracted with more 6:1 solution This wash with dilute brine Then the organic phase was dried (sodium sulfate) concentrated under vacuum

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

Procedure: To a solution of (1R,2R)-2-pent-4-en-1-ylcyclopentanol (105 mg, 0.68 mmol) in MeCN (1.4 mL) was added N,N′-disuccinimidyl carbonate (174 mg, 0.68 mmol) and Et3N (0.19 mL, 1.36 mmol) and the mixture was stirred at 40 C for 20 hours. The reaction mixture was cooled, concentrated and purified by silica chromatography (gradient elution 0 to 100% EtOAc in hexane). LCMS (M+Na)+=318.1. The reaction mixture was cooled concentrated purified by silica chromatography (gradient elution 0 to 100% EtOAc in hexane)

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

Procedure: The same procedure used in the preparation of Example C was followed substituting an equivalent amount of DL-ethyl 3-amino-3-pyridyl propionate for ethyl beta-alanine hydrochloride. N,N'-Disuccinimidyl carbonate (14 g, 5.5 mmol) was added to 3-nitro-benzoyl glycine (10 g, 4.5 mmol) in dry dimethylformamide (30 mL) followed by dimethylaminopyridine (200 mg). After a period of 1 hour DL-ethyl 3-amino-3-(3-pyridyl) propionate dihydrochloride (13 g, 4.6 mmol) in 20% aqueous potassium carbonate (50 mL) was added in one portion. After complete reaction the product was collected by filtration (11.5 g, 80% yield). MS and 1H-NMR were consistent with the proposed structure. The same procedure used in the preparation of Example C After complete reaction the product was collected by filtration (11.5 g, 80% yield)

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

Procedure: N,N'-Disuccinimidyl carbonate (14 g, 5.5 mmol) was added to 3-nitrobenzoyl glycine (10 g, 4.5 mmol) of Example BB in dry dimethylformamide (30 mL) followed by N,N-dimethylaminopyridine (200 mg). After a period of 1 hour beta-alanine ethyl ester hydrochloride (7 g, 4.6 mmol) in 20% aqueous potassium carbonate (50 mL) was added in one portion. After complete reaction the product was collected by filtration (14 g, 97% yield). 1H-NMR (d6 -DMSO) δ, 1.18 (t, 3H, J=7.2 Hz), 2.46 (t, 2H, J=7.0), 3.34 (q, 2H, J1 =6.7 Hz, J2 =12.6 Hz), 3.87 (d, 2H, J=5.9 Hz), 4.05 (q, 2H, J1 =7.4 Hz, J2 =14.2 Hz), 7.8 (t, 1H, J=8.0 Hz), 8.1 (t, 1H, J=5.6 Hz), 8.35 (m, 2H), 8.71 (s, 1H), 9.22 (bs, 1H). After complete reaction the product was collected by filtration (14 g, 97% yield)

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

Procedure: To a solution of 2.5 g (22.9 mmol) of 3-pyridylcarbinol in 100 mL of anhydrous acetonitrile was added 8.8 g (34.4 mmol) of N,N'-disuccinimidyl carbonate and 5.55 mL (68.7 mmol) of pyridine. The solution was stirred for 1 hour and then concentrated in vacuo. The residue was dissolved in ethyl acetate, then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated to afford 5.3 g of N-Hydroxysuccinimide-3-pyridylmethyl carbonate, mass spectrum m/e=251 (M+H), which was used directly in the next step without purification. concentrated in vacuo The residue was dissolved in ethyl acetate washed with saturated sodium bicarbonate, brine dried over magnesium sulfate filtered concentrated

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

Procedure: N,N′-Disuccinimidylcarbonate (5.49 g, 21.44 mmol, 1.1 eq) is added at room temperature to a stirred solution of N-(4-aminophenyl)({2-[(tert-butoxy)carbonyl-amino]ethyl}amino)carboxamide (6.75 g, 19.49 mmol, 1.0 eq) in CH3CN (350 mL).

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

Procedure: N,N′-Disuccinimidylcarbonate (16.20 g, 63.26 mmol, 1.1 eq) is added at room temperature to a stirred solution of N-(4-aminophenyl)(fluoren-9-ylmethoxy)carboxamide (20.00 g, 60.53 mmol, 1.0 eq) in CH3CN (1100 mL). After stirring overnight at room temperature, the reaction mixture is filtered to afford 28.50 g of the expected crude product as a white powder. the reaction mixture is filtered