2-[(2-methylpropan-2-yl)oxycarbonylamino]oxyacetic acid

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

Procedure: [(1,1-Dimethylethoxy)carbonyl]aminooxyacetic acid, methyl ester (18.0 g, 0.087 mole) and potassium hydroxide (7.4 g, 0.13 mole) were stirred in 60 ml of methanol for one hour at ambient temperatures. The mixture was neutralized with concentrated hydrochloric acid and evaporated to dryness in vacuo. The residue was taken up in 100 ml of water and acidified to pH 2.5. Extraction with ethyl acetate, drying over magnesium sulfate and evaporation gave the title compound as 6.8 g of a colorless solid, m.p. 95°-98° C. evaporated to dryness in vacuo Extraction with ethyl acetate drying over magnesium sulfate and evaporation

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

Procedure: A solution of 2-(tert-butoxycarbonylaminooxy)acetic acid (87a, 1 g, 5.23 mmol) in anhydrous THF was chilled in an ice bath and N-methylmorpholine (863 μL, 7.85 mmol) and isobutyl chloroformate (746 μL, 5.75 mmol) were added sequentially. The mixture was stirred under an N2 atmosphere for 20 min. A 33 wt % solution of methanamine in ethanol (1.3 mL, 10.46 mmol) was added to the reaction which was subsequently allowed to warm to room temperature with stirring overnight. The THF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with H2O×2 and dried over anhydrous Na2SO4. The ethyl acetate was removed in vacuo to yield tert-butyl 2-(methylamino)-2-oxoethoxycarbamate (87b, 775 mg, 3.80 mmol). with stirring overnight The THF was removed in vacuo the residue was partitioned between ethyl acetate and water The organic phase was washed with H2O×2 dried over anhydrous Na2SO4 The ethyl acetate was removed in vacuo

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

Procedure: (S)-3-[2-(tert-Butoxycarbonylaminooxy)acetyl]amino-1-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine can be prepared from hydrochloride of the compound prepared in Example 19-2 by using 2-(tert-butoxycarbonylaminooxy)acetic acid in the method of Example 56-1 instead of 2-methoxyacetic acid, and the protective group of the obtained compound can be removed according to the method described in Example 1-1, Step B to obtain the title compound. the protective group of the obtained compound can be removed

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

Procedure: tert-Butyloxycarbonylaminoxy acetic acid was dissolved in ice-cooled ethyl acetate or acetonitrile and treated with N,N′-dicyclohexylcarbodiimide (1.0 equivalent) and N-hydroxysuccinimide (1.0 equivalent). The reaction mixture was stirred at room temperature overnight. The N,N′-dicyclohexylurea formed was removed by filtration and the filtrate was evaporated to dryness in vacuo. The crude Boc-AOA-OSu was either used directly in the next step or purified by recrystallisation from chloroform. Adopted from Kurth et al. J. Med. Chem. 1993, 36, 1255.

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

Procedure: tert-Butyloxycarbonylaminoxy acetic acid was dissolved in ice-cooled ethyl acetate or acetonitrile and treated with N,N′-dicyclohexylcarbodiimide (1.0 equivalent) and N-hydroxysuccinimide (1.0 equivalent). The reaction mixture was stirred at room temperature overnight. The N,N′-dicyclohexylurea formed was removed by filtration and the filtrate was evaporated to dryness in vacuo. The crude Boc-AOA-OSu was either used directly in the next step or purified by recrystallisation from chloroform. Adopted from Kurth et al. J. Med. Chem. 1993, 36, 1255.

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

Procedure: tert-Butyloxycarbonylaminoxy acetic acid was dissolved in ice-cooled ethyl acetate or acetonitrile and treated with N,N′-dicyclohexylcarbodiimide (1.0 equivalent) and N-hydroxysuccinimide (1.0 equivalent). The reaction mixture was stirred at room temperature overnight. The N,N′-dicyclohexylurea formed was removed by filtration and the filtrate was evaporated to dryness in vacuo. The crude Boc-AOA-OSu was either used directly in the next step or purified by recrystallisation from chloroform. Adopted from Kurth et al. J. Med. Chem. 1993, 36, 1255.

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

Procedure: A further embodiment of the invention according to the above reaction of obtaining formula (A) is dissolving (Boc-aminoxy)acetic acid, (G), in acetic anhydride and heating the mixture to a temperature in the range of about 40° C. to about 70° C. for about 48 hours to about 72 hours to form (Boc-aminooxy)acetic anhydride, (H). A further embodiment of the invention according to the above reaction heating the mixture to a temperature in the range of about 40° C. to about 70° C. for about 48 hours to about 72 hours

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

Procedure: A solution of 2-(tert-butoxycarbonylaminooxy)acetic acid (87a, 1 g, 5.23 mmol) in anhydrous THF was chilled in an ice bath and N-methylmorpholine (863 μL, 7.85 mmol) and isobutyl chloroformate (746 μL, 5.75 mmol) were added sequentially. The mixture was stirred under an N2 atmosphere for 20 min. A 33 wt % solution of methanamine in ethanol (1.3 mL, 10.46 mmol) was added to the reaction which was subsequently allowed to warm to room temperature with stirring overnight. The THF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with H2O×2 and dried over anhydrous Na2SO4. The ethyl acetate was removed in vacuo to yield tert-butyl 2-(methylamino)-2-oxoethoxycarbamate (87b, 775 mg, 3.80 mmol). with stirring overnight The THF was removed in vacuo the residue was partitioned between ethyl acetate and water The organic phase was washed with H2O×2 dried over anhydrous Na2SO4 The ethyl acetate was removed in vacuo

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of [(1,1-dimethylethoxy)carbonyl]aminooxy acetic acid (Example 7b, 1.0g, 5.2 mmole) and N-methylmorpholine (0.57 ml, 5.2 mmole) in 10 ml of dimethylformamide at -10° C. was treated dropwise with isobutylchloroformate (0.74 ml, 5.7 mmole). The mixture was stirred at -10° C. for 1 hour, then was treated with a suspension of 2,3-di(phenylmethoxy)-5-sulfobenzoic acid hydrazide (2.24g, 5.2 mmole) in 20 ml of dimethylformamide followed by the dropwise addition of a solution of N-methylmorpholine (0.86 ml, 7.8 mmole) and 4-(N, N-dimethylamino)pyridine (30 mg) in 10 ml of dimethylformamide over 20 minutes. The reaction was stirred for 1 hour at 0° C., then was allowed to warm to ambient temperatures overnight. Evaporation in vacuo gave an oil which was taken up in 30 ml of water. The pH was adjusted to 2 with aqueous hydrochloric acid and the oily product was extracted into ethyl acetate. Drying over magnesium sulfate and evaporation gave a residue which crystallized with hexane. The solid was filtered and dried to give 2.3g. mp 103°-105° C. The reaction was stirred for 1 hour at 0° C. to warm to ambient temperatures overnight Evaporation in vacuo gave an oil which the oily product was extracted into ethyl acetate Drying over magnesium sulfate and evaporation gave a residue which crystallized with hexane The solid was filtered dried to give 2.3g

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

Procedure: [(1,1-Dimethylethoxy)carbonyl]aminooxyacetic acid, methyl ester (18.0 g, 0.087 mole) and potassium hydroxide (7.4 g, 0.13 mole) were stirred in 60 ml of methanol for one hour at ambient temperatures. The mixture was neutralized with concentrated hydrochloric acid and evaporated to dryness in vacuo. The residue was taken up in 100 ml of water and acidified to pH 2.5. Extraction with ethyl acetate, drying over magnesium sulfate and evaporation gave the title compound as 6.8 g of a colorless solid, m.p. 95°-98° C. evaporated to dryness in vacuo Extraction with ethyl acetate drying over magnesium sulfate and evaporation

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

Procedure: [(1,1-Dimethylethoxy)carbonyl]aminooxyacetic acid, methyl ester (18.0 g, 0.087 mole) and potassium hydroxide (7.4 g, 0.13 mole) were stirred in 60 ml of methanol for one hour at ambient temperatures. The mixture was neutralized with concentrated hydrochloric acid and evaporated to dryness in vacuo. The residue was taken up in 100 ml of water and acidified to pH 2.5. Extraction with ethyl acetate, drying over magnesium sulfate and evaporation gave the title compound as 6.8 g of a colorless solid, m.p. 95°-98° C. evaporated to dryness in vacuo Extraction with ethyl acetate drying over magnesium sulfate and evaporation

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

Procedure: A solution of 2-(tert-butoxycarbonylaminooxy)acetic acid (87a, 1 g, 5.23 mmol) in anhydrous THF was chilled in an ice bath and N-methylmorpholine (863 μL, 7.85 mmol) and isobutyl chloroformate (746 μL, 5.75 mmol) were added sequentially. The mixture was stirred under an N2 atmosphere for 20 min. A 33 wt % solution of methanamine in ethanol (1.3 mL, 10.46 mmol) was added to the reaction which was subsequently allowed to warm to room temperature with stirring overnight. The THF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with H2O×2 and dried over anhydrous Na2SO4. The ethyl acetate was removed in vacuo to yield tert-butyl 2-(methylamino)-2-oxoethoxycarbamate (87b, 775 mg, 3.80 mmol). with stirring overnight The THF was removed in vacuo the residue was partitioned between ethyl acetate and water The organic phase was washed with H2O×2 dried over anhydrous Na2SO4 The ethyl acetate was removed in vacuo