(2,5-dioxopyrrolidin-1-yl) 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-Boc-β-Ala-OH (1 g, 5.29 nmol), N-hydroxysuccinimide (0.9 g, 7.82 mmol) in DMF (10 mL) were added HOBt (0.7 g, 5.25 mmol) and EDCI.HCl (1 g, 5.23 mmol) at 5° C. The reaction mixture was warmed to RT and stirred for 16 h. The progress of the reaction was monitored by TLC. The reaction was quenched with water and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (3×100 mL), brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was triturated with ether (2×25 mL) to afford N-Boc-β-Ala-OSu (1.1 g, crude) as white solid. 1H NMR (500 MHz, CDCl3): δ 5.10 (bs, 1H), 3.52 (q, J=6.0 Hz, 2H), 2.85-2.82 (m, 6H), 1.31 (s, 9H). The reaction was quenched with water extracted with ethyl acetate (2×150 mL) The combined organic layers were washed with water (3×100 mL), brine (150 mL) dried over anhydrous Na2SO4 concentrated under reduced pressure The crude compound was triturated with ether (2×25 mL)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using 5.60 g of Boc-Asn-Leu-OEt and 5.60 g of Boc-β-Ala-OSu, the same procedure as in Reference Example 35 was repeated to obtain 4.71 g (yield: 70.6%) of the above objective compound having a melting point of 148°-153° C.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl (5S)-5-amino-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-6-oxohexylcarbamate (1.60 g) and triethylamine (0.47 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (1.34 g). The mixture was stirred at room temperature for 15 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (5S)-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-oxohexylcarbamate (2.09 g) as an oil. The crude product was used directly in the next step without further purification. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution The organic layer was dried over anhydrous magnesium sulfate filtered concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl (5S)-5-amino-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-6-oxohexylcarbamate (1.60 g) and triethylamine (0.47 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (1.34 g). The mixture was stirred at room temperature for 15 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (5S)-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-oxohexylcarbamate (2.09 g) as an oil. The crude product was used directly in the next step without further purification. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution The organic layer was dried over anhydrous magnesium sulfate filtered concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl (4S)-4-amino-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-oxopentylcarbamate (4.90 g) and triethylamine (1.52 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (4.26 g). The mixture was stirred at room temperature for 17 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-oxopentylcarbamate as an oil. The crude product was used directly in the next step without further purification. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution The organic layer was dried over anhydrous magnesium sulfate filtered concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl (4S)-4-amino-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-oxopentylcarbamate (4.90 g) and triethylamine (1.52 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (4.26 g). The mixture was stirred at room temperature for 17 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-oxopentylcarbamate as an oil. The crude product was used directly in the next step without further purification. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution The organic layer was dried over anhydrous magnesium sulfate filtered concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of N-Boc-β-Ala-OH (1 g, 5.29 nmol), N-hydroxysuccinimide (0.9 g, 7.82 mmol) in DMF (10 mL) were added HOBt (0.7 g, 5.25 mmol) and EDCI.HCl (1 g, 5.23 mmol) at 5° C. The reaction mixture was warmed to RT and stirred for 16 h. The progress of the reaction was monitored by TLC. The reaction was quenched with water and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (3×100 mL), brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was triturated with ether (2×25 mL) to afford N-Boc-β-Ala-OSu (1.1 g, crude) as white solid. 1H NMR (500 MHz, CDCl3): δ 5.10 (bs, 1H), 3.52 (q, J=6.0 Hz, 2H), 2.85-2.82 (m, 6H), 1.31 (s, 9H). The reaction was quenched with water extracted with ethyl acetate (2×150 mL) The combined organic layers were washed with water (3×100 mL), brine (150 mL) dried over anhydrous Na2SO4 concentrated under reduced pressure The crude compound was triturated with ether (2×25 mL)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using 5.60 g of Boc-Asn-Leu-OEt and 5.60 g of Boc-β-Ala-OSu, the same procedure as in Reference Example 35 was repeated to obtain 4.71 g (yield: 70.6%) of the above objective compound having a melting point of 148°-153° C.

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir: