* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃;
A solution of ethyl chlorocarbonate (8.9 ml, 93 mmol) in THF (250 ml) was added slowly to a mixture of 3-amino-4, 6-dihydro-lH-pyrrolo [3, 4-C] ole-5-carboxylic acid tert-butyl ester (20 g, 89 mmol) and DIISOPROPYLETHYLAMINE (DIEA, 92 ml, 528 mmol) in THF (500 ml) at 0-5°C. The reaction was kept at the same temperature for two hours then allowed to reach room temperature and stirred overnight. The obtained mixture was evaporated to dryness under vacuum. The resulting residue was extracted with ethyl acetate and water. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The mixture was purified by flash-chromatography (eluent : ethyl ACETATE/EYCLOHEXANE 4/6 to 7/3) to give 19 g (72percent yield) of the title compound as a white solid. 1H-NMR (400 MHZ, DMSO-S6) ppm: 10. 06 (S, broad signal, 2H), 4. 4-4. 05 (M, 6H), 1.27 (t, 3H) 1 (2, 9H).
72%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran
EXAMPLE 27 Preparation of 3-Amino-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester A solution of ethyl chlorocarbonate (8.9 ml, 93 mmol) in THF (250 ml) was added slowly to a mixture of 3-amino-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (20 g, 89 mmol) and DIEA (92 ml, 528 mmol) in THF (500 ml) at 0-5° C. The reaction was kept at the same temperature for two hours then allowed to reach r.t. and stirred overnight. The obtained mixture was evaporated to dryness under vacuum. The resulting residue was extracted with AcOEt and water. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The mixture was purified by flash-chromatography (eluent: ethyl acetate/cyclohexane 4/6 to 7/3) to give 19 g (72percent yield) of the title compound as a white solid.
62%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 13 h;
To a solution of tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate 1 (40.00 g, 0.18 mol) and ethyldiisopropylamine (DIEA) (138.00 g, 1.06 mol) in dry THF (700 mL) was added dropwise a solution of ethyl chlorocarbonate (20.20 g, 0.19 mol) in dry THF (250 mL) over a period of 1 h at 0-5 °C. The reaction mixture was stirred for 12 h at room temperature and concentrated under reduced pressure. The residue was treated with ethyl acetate (500 mL), washed successively with water and saturated saline, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was recrystallized from dichloromethane / ethyl acetate /petroleum ether (40 mL: 60 mL: 160 mL) to afford the title compound 2 (32.70 g, 62percent) as a white solid, mp: 167-168 °C.
60.7%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃;
Synthesis of compound 9b Ethyl chloroformate (4.5 ml, 46.5 mmol) was dissolved in tetrahydrofuran (100 ml), with ice bath, compound 8b (10 g, 44.5 mmol) and DIPEA (46 ml, 264 mmol) were dissolved in tetrahydrofuran (250 ml), at 0-5 °C add the drops into reaction solution, then rise to the room temperature for reaction of 16 hours, then vacuum evaporate the reaction solution and dissolve the residue with ethyl acetate, and wash the organic phase with water, dry the organic phase with sodium sulfate, vacuum evaporate the solvent with lower pressure, purify the residue with silica gel layer chromatography (ethyl acetate: petroleum ester=1:3), to give the white solid(compound 9b : 8.0 g, 60.7percent yield). 1H NMR (400 MHz, CD3OD) δ 4.72 (s, 2H), 4.40 (q, J=7.2Hz, 2H), 4.12 (d, J=7.2Hz, 2H), 1.53 (s, 9H), 1.40 (t, J=6.8Hz, 3H).
1.62 g
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 5℃;
Step 1. 5-(tert-butyl) 1-ethyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate A solution of ethyl chloroformate (0.90 ml; 0.01 mol; 1.05 eq.) in 20 ml of THF was slowly added to a mixture of tert-butyl 3-amino-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carboxylate (2.00 g; 0.01 mol; 1.00 eq.) and Hunig's base (8.81 ml; 0.05 mol; 6.00 eq.) in tetrahydrofuran (50.00 ml) at 0-5° C. The reaction was kept at the same temperature for two hours, then allowed to reach room temperature and stirred overnight. The reaction mixture was evaporated to dryness and the resulting residue was partitioned in ethyl acetate and water. The organic phase was separated and the aqueous layer was back extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash-chromatography using 0-90percent EtOAc in hexanes to give the desired 5-(tert-butyl) 1-ethyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (1.62 g). 1H NMR (400 MHz, DMSO-d6) δ 5.67 (d, J=2.2 Hz, 2H), 4.44 (dt, J=10.7, 3.1 Hz, 2H), 4.25 (q, J=7.1 Hz, 2H), 4.15 (dt, J=18.3, 3.2 Hz, 2H), 1.42 (s, 9H), 1.26 (td, J=7.1, 1.4 Hz, 3H). MS (M+H)+ found for C13H20N4O4: 296.5.
30 g
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃;
(6) 24.8 g (0.11 mol) of the general formula (16) was added to 200 mL of THF,DIEA 18.3 mL (0.11 mol) was added with stirring under ice-salt bath,And 10.5 mL (0.11 mol) of ethyl chloroformate diluted with THF was added dropwise thereto. The temperature was controlled to 0 ° C or lower,Reaction 5-6 h, TLC monitoring. Post-treatment, concentration under reduced pressure, extraction with methylene chloride,Washed with saturated NaCl, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the compound of formula (17) as a pale yellow solid,30.0 g.
3.2 g
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 2.16667 h;
To a solution of tert-butyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-5(lH)-carboxylate (2.600 g, 11.607 mmol) in THF (30 ml) was added DIPEA (11.8 ml, 69.6 mmol) at 0°C. Ethyl chloroformate (1.11 ml, 11.72 mmol) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 10 min and then at rt for 2 h. The reaction mixture was poured into water (60 ml) and extracted with EtOAc (3 x 60 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (2-3percent MeOH in DCM) yielding 5-tert-butyl 1-ethyl 3-amino-4,6- dihydropyrrolo[3,4-c]pyrazole-l,5-dicarboxylate (3.200 g, 10.81 mmol). LCMS: Method 1, 1.986, MS: ES+ 297.43.
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 8, p. 3080 - 3084
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 4, p. 1084 - 1090
[3] Patent: WO2004/80457, 2004, A1, . Location in patent: Page/Page column 28-29
[4] Patent: US2003/171357, 2003, A1,
[5] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 14, p. 4273 - 4278
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6947 - 6951,5
[7] Patent: EP3133069, 2017, A1, . Location in patent: Paragraph 0073
[8] Journal of Medicinal Chemistry, 2006, vol. 49, # 24, p. 7247 - 7251
[9] Patent: WO2005/5427, 2005, A1, . Location in patent: Page/Page column 20
[10] Patent: US2015/315198, 2015, A1, . Location in patent: Paragraph 1653; 1654
[11] Patent: CN104072498, 2016, B, . Location in patent: Paragraph 0118; 0151
[12] Patent: WO2017/158381, 2017, A1, . Location in patent: Page/Page column 57
2
[ 25544-75-6 ]
[ 175463-32-8 ]
[ 398495-65-3 ]
Yield
Reaction Conditions
Operation in experiment
40.3 g
at 60℃;
5) 33.1 g (0.16 mol) of the general formula (14) was added to 200 mL of anhydrous ethanol,22.4 g (0.16 mol) of ethyl hydrazinecarboxylate hydrochloride was added in portions, and the reaction was carried out at 60 ° C for 4 to 5 hours. The reaction was monitored by TLC.The filtrate was concentrated under reduced pressure to give 40.3 g of a white solid of general formula (17).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃;
A solution of ethyl chlorocarbonate (8.9 ml, 93 mmol) in THF (250 ml) was added slowly to a mixture of 3-amino-4, 6-dihydro-lH-pyrrolo [3, 4-C] ole-5-carboxylic acid tert-butyl ester (20 g, 89 mmol) and DIISOPROPYLETHYLAMINE (DIEA, 92 ml, 528 mmol) in THF (500 ml) at 0-5C. The reaction was kept at the same temperature for two hours then allowed to reach room temperature and stirred overnight. The obtained mixture was evaporated to dryness under vacuum. The resulting residue was extracted with ethyl acetate and water. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The mixture was purified by flash-chromatography (eluent : ethyl ACETATE/EYCLOHEXANE 4/6 to 7/3) to give 19 g (72% yield) of the title compound as a white solid. 1H-NMR (400 MHZ, DMSO-S6) ppm: 10. 06 (S, broad signal, 2H), 4. 4-4. 05 (M, 6H), 1.27 (t, 3H) 1 (2, 9H).
72%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;
EXAMPLE 27 Preparation of 3-Amino-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester A solution of ethyl chlorocarbonate (8.9 ml, 93 mmol) in THF (250 ml) was added slowly to a mixture of <strong>[398491-59-3]3-amino-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester</strong> (20 g, 89 mmol) and DIEA (92 ml, 528 mmol) in THF (500 ml) at 0-5 C. The reaction was kept at the same temperature for two hours then allowed to reach r.t. and stirred overnight. The obtained mixture was evaporated to dryness under vacuum. The resulting residue was extracted with AcOEt and water. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The mixture was purified by flash-chromatography (eluent: ethyl acetate/cyclohexane 4/6 to 7/3) to give 19 g (72% yield) of the title compound as a white solid.
62%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 13.0h;
To a solution of <strong>[398491-59-3]tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate</strong> 1 (40.00 g, 0.18 mol) and ethyldiisopropylamine (DIEA) (138.00 g, 1.06 mol) in dry THF (700 mL) was added dropwise a solution of ethyl chlorocarbonate (20.20 g, 0.19 mol) in dry THF (250 mL) over a period of 1 h at 0-5 C. The reaction mixture was stirred for 12 h at room temperature and concentrated under reduced pressure. The residue was treated with ethyl acetate (500 mL), washed successively with water and saturated saline, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was recrystallized from dichloromethane / ethyl acetate /petroleum ether (40 mL: 60 mL: 160 mL) to afford the title compound 2 (32.70 g, 62%) as a white solid, mp: 167-168 C.
60.7%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃;
Synthesis of compound 9b Ethyl chloroformate (4.5 ml, 46.5 mmol) was dissolved in tetrahydrofuran (100 ml), with ice bath, compound 8b (10 g, 44.5 mmol) and DIPEA (46 ml, 264 mmol) were dissolved in tetrahydrofuran (250 ml), at 0-5 C add the drops into reaction solution, then rise to the room temperature for reaction of 16 hours, then vacuum evaporate the reaction solution and dissolve the residue with ethyl acetate, and wash the organic phase with water, dry the organic phase with sodium sulfate, vacuum evaporate the solvent with lower pressure, purify the residue with silica gel layer chromatography (ethyl acetate: petroleum ester=1:3), to give the white solid(compound 9b : 8.0 g, 60.7% yield). 1H NMR (400 MHz, CD3OD) delta 4.72 (s, 2H), 4.40 (q, J=7.2Hz, 2H), 4.12 (d, J=7.2Hz, 2H), 1.53 (s, 9H), 1.40 (t, J=6.8Hz, 3H).
A solution of ethyl chlorocarbonate (8. 9 ml, 93 MMOL) in tetrahydrofuran (THF, 250 ml) was slowly added to a mixture of tert-butyl 3-AMINO-4, 6-dihydropyrrolo [3, 4-CPYRAZOLE-5 (1 H)- CARBOXYLATE (20 G, 89 MMOL) and diisopropylethylamine (DIEA, 92 ml, 528 MMOL) in THF (500 ML) at 0-5 C. The reaction was kept at the same temperature for two hours then allowed to reach room temperature and stirred overnight. The obtained mixture was evaporated to dryness under vacuum, and the resulting residue extracted with ethyl acetate (AcOEt) and water. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The mixture was purified by flash-chromatography (eluent : ethyl acetate/cyclohexane 4/6 to 7/3) to give 19 G of the title compound as a white solid. [M+H] + 297
1.62 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 5℃;
Step 1. 5-(tert-butyl) 1-ethyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylateA solution of ethyl chloroformate (0.90 ml; 0.01 mol; 1.05 eq.) in 20 ml of THF was slowly added to a mixture of <strong>[398491-59-3]tert-butyl 3-amino-1H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carboxylate</strong> (2.00 g; 0.01 mol; 1.00 eq.) and Hunig's base (8.81 ml; 0.05 mol; 6.00 eq.) in tetrahydrofuran (50.00 ml) at 0-5 C. The reaction was kept at the same temperature for two hours, then allowed to reach room temperature and stirred overnight. The reaction mixture was evaporated to dryness and the resulting residue was partitioned in ethyl acetate and water. The organic phase was separated and the aqueous layer was back extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash-chromatography using 0-90% EtOAc in hexanes to give the desired 5-(tert-butyl) 1-ethyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (1.62 g). 1H NMR (400 MHz, DMSO-d6) delta 5.67 (d, J=2.2 Hz, 2H), 4.44 (dt, J=10.7, 3.1 Hz, 2H), 4.25 (q, J=7.1 Hz, 2H), 4.15 (dt, J=18.3, 3.2 Hz, 2H), 1.42 (s, 9H), 1.26 (td, J=7.1, 1.4 Hz, 3H). MS (M+H)+ found for C13H20N4O4: 296.5.
30 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃;
(6) 24.8 g (0.11 mol) of the general formula (16) was added to 200 mL of THF,DIEA 18.3 mL (0.11 mol) was added with stirring under ice-salt bath,And 10.5 mL (0.11 mol) of ethyl chloroformate diluted with THF was added dropwise thereto. The temperature was controlled to 0 C or lower,Reaction 5-6 h, TLC monitoring. Post-treatment, concentration under reduced pressure, extraction with methylene chloride,Washed with saturated NaCl, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the compound of formula (17) as a pale yellow solid,30.0 g.
3.2 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 2.16667h;
To a solution of tert-butyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-5(lH)-carboxylate (2.600 g, 11.607 mmol) in THF (30 ml) was added DIPEA (11.8 ml, 69.6 mmol) at 0C. Ethyl chloroformate (1.11 ml, 11.72 mmol) was added dropwise to the reaction mixture at 0C. The reaction mixture was stirred at 0C for 10 min and then at rt for 2 h. The reaction mixture was poured into water (60 ml) and extracted with EtOAc (3 x 60 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (2-3% MeOH in DCM) yielding 5-tert-butyl 1-ethyl 3-amino-4,6- dihydropyrrolo[3,4-c]pyrazole-l,5-dicarboxylate (3.200 g, 10.81 mmol). LCMS: Method 1, 1.986, MS: ES+ 297.43.
[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-acetyl chloride[ No CAS ]
3-{2-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-acetylamino}-4,6-dihydro-pyrrolo[3,4-<i>c</i>]pyrazole-1,5-dicarboxylic acid 5-<i>tert</i>-butyl ester 1-ethyl ester[ No CAS ]
3-[(benzo[1,3]dioxole-5-carbonyl)-amino]-4,6-dihydro-pyrrolo[3,4-<i>c</i>]pyrazole-1,5-dicarboxylic acid 5-<i>tert</i>-butyl ester 1-ethyl ester[ No CAS ]
5-tert-butyl 1-ethyl 3-(4-fluorobenzamido)pyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 13.0h;
General procedure: To a solution of 2 (13.00 g, 43.90 mmol) and DIEA ( 33.60 g, 260.00 mmol) in dry THF (400 mL) was added dropwise a solution of corresponding acyl chlorides (48.30 mmol) in dry THF (50 mL) over a period of 1 h at room temperature. The reaction mixture was stirred for 12 h at the same temperature and concentrated under reduced pressure. The residue was treated with ethyl acetate / saturated saline (400 mL: 400 mL) and stayed for 2 h, and then filtered. The precipitate was washed with diethyl ether (30 mL), and dried in vacuo to yield the title compounds 3a-d. 3e was obtained by flash chromatography (180 g silica gel, petroleum ether/AcOEt, 0-30%, V/V).
5-tert-butyl 1-ethyl-3-benzamidopyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 13.0h;
General procedure: To a solution of 2 (13.00 g, 43.90 mmol) and DIEA ( 33.60 g, 260.00 mmol) in dry THF (400 mL) was added dropwise a solution of corresponding acyl chlorides (48.30 mmol) in dry THF (50 mL) over a period of 1 h at room temperature. The reaction mixture was stirred for 12 h at the same temperature and concentrated under reduced pressure. The residue was treated with ethyl acetate / saturated saline (400 mL: 400 mL) and stayed for 2 h, and then filtered. The precipitate was washed with diethyl ether (30 mL), and dried in vacuo to yield the title compounds 3a-d. 3e was obtained by flash chromatography (180 g silica gel, petroleum ether/AcOEt, 0-30%, V/V).
5-tert-butyl 1-ethyl 3-(4-methylbenzamido)pyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 13.0h;
General procedure: To a solution of 2 (13.00 g, 43.90 mmol) and DIEA ( 33.60 g, 260.00 mmol) in dry THF (400 mL) was added dropwise a solution of corresponding acyl chlorides (48.30 mmol) in dry THF (50 mL) over a period of 1 h at room temperature. The reaction mixture was stirred for 12 h at the same temperature and concentrated under reduced pressure. The residue was treated with ethyl acetate / saturated saline (400 mL: 400 mL) and stayed for 2 h, and then filtered. The precipitate was washed with diethyl ether (30 mL), and dried in vacuo to yield the title compounds 3a-d. 3e was obtained by flash chromatography (180 g silica gel, petroleum ether/AcOEt, 0-30%, V/V).
5-tert-butyl 1-ethyl-3-(4-methoxybenzamido)pyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 13.0h;
General procedure: To a solution of 2 (13.00 g, 43.90 mmol) and DIEA ( 33.60 g, 260.00 mmol) in dry THF (400 mL) was added dropwise a solution of corresponding acyl chlorides (48.30 mmol) in dry THF (50 mL) over a period of 1 h at room temperature. The reaction mixture was stirred for 12 h at the same temperature and concentrated under reduced pressure. The residue was treated with ethyl acetate / saturated saline (400 mL: 400 mL) and stayed for 2 h, and then filtered. The precipitate was washed with diethyl ether (30 mL), and dried in vacuo to yield the title compounds 3a-d. 3e was obtained by flash chromatography (180 g silica gel, petroleum ether/AcOEt, 0-30%, V/V).
5-tert-butyl 1-ethyl-3-(2-phenylacetamido)pyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 13.0h;
General procedure: To a solution of 2 (13.00 g, 43.90 mmol) and DIEA ( 33.60 g, 260.00 mmol) in dry THF (400 mL) was added dropwise a solution of corresponding acyl chlorides (48.30 mmol) in dry THF (50 mL) over a period of 1 h at room temperature. The reaction mixture was stirred for 12 h at the same temperature and concentrated under reduced pressure. The residue was treated with ethyl acetate / saturated saline (400 mL: 400 mL) and stayed for 2 h, and then filtered. The precipitate was washed with diethyl ether (30 mL), and dried in vacuo to yield the title compounds 3a-d. 3e was obtained by flash chromatography (180 g silica gel, petroleum ether/AcOEt, 0-30%, V/V).
3-[(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-amino]-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 0.5h;
A: starting materials i) 3-[(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-mdole-6-carbonyl)-amino]-4,6- dihydro-pyrrolo[3>4-c]pyrazole-l,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carboxylic acid (3.0 g, 14.62 mmol) was dissolved in thionylchloride (19.1 mL, 163 mmol) and after addition of N,N- dimethylformamide (DMF) (200 muL) the mixture was refluxed for 1.5 hours. The volatiles were carefully removed under reduced pressure and the resulting 3,3- dimethyl-2-oxo-2,3-dihydro-lH-indole-6-carbonyl chloride was added portionwise to a mixture of 3-amino-4,6-dihydro-pyrrolo[3,4-c]pyrazole-l,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (4.33 g, 14.62 mmol) in dry dichloromethane (DCM) (40 mL) and ethyl-diisopropyl-amine (DIEA) (2.53 mL, 14.62 mmol). The resulting mixture was stirred for 30 minutes, washed with water (20 mL) and brine (20 mL) <n="23"/>and evaporated to dryness. Purification by flash chromatography over silica gel eluting with ethyl acetate/«-heptane (2:1), afforded the title compound as a white solid (5.5 g, 78 %).MS: M = 482.0 (ESI-)1H-NMR (400 MHz, DMSO): delta (ppm) = 1.28 (s, 6H), 1.34 (t, 3H), 1.46 (s, 9H),4.41 (q, 2H), 4.51 (br, 2H, rotamers), 4.60 (br, 2H, rotamers), 7.42 (m, IH), 7.47 (s, IH), 7.71 (m, IH), 10.58 (s, IH), 11.45 (s, IH)
3-[(benzo[1,3]dioxole-5-carbonyl)-amino]-5-isopropylcarbamoyl-5,6-dihydro-4<i>H</i>-pyrrolo[3,4-<i>c</i>]pyrazole-1-carboxylic acid ethyl ester[ No CAS ]
5-butylcarbamoyl-3-[2-(4-pyrrolidin-1-yl-phenyl)-acetylamino]-5,6-dihydro-4<i>H</i>-pyrrolo[3,4-<i>c</i>]pyrazole-1-carboxylic acid ethyl ester[ No CAS ]
5-butylcarbamoyl-3-{2-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-acetylamino}-5,6-dihydro-4<i>H</i>-pyrrolo[3,4-<i>c</i>]pyrazole-1-carboxylic acid ethyl ester[ No CAS ]
With iodine; isopentyl nitrite; In dichloromethane; at 20 - 28℃; for 1.0h;
Isoamyl nitrite (18.2 ml, 135,2 mmol) was slowly added to a mixture of Iodine (20.58 g, [81.] 11 mmol) in 145 mL of anhydrous dichloromethane, at [+22C.] To this dark mixture a solution [OF 5-TERT-BUTYLOXYCARBONYL-1-ETHOXYCARBONYL-3-AMINO-4,] 6- dihydropyrrolo [3,4-c] pyrazole (20.03 g, 67.6 mmol) in 140 mL of dichloromethane was added dropwise over 100 min at [+22C.] The internal temperature rose to [+28C] and gas evolved during the addition. After 1 hour stirring at room temperature, the reaction mixture was slowly poured in [800ML] of 10% sodium metabisulfite. The phases were separated and the aqueous was extracted twice with 300 mL dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and the solvent evaporated under vacuum. This raw material was purified by flash chromatography eluting with 20: 80 EtOAc/cyclohexane. A light yellow product (25.5 g) was obtained which was finally purified with MTBE (60 mL) and n-hexane (60 mL): 21. [8] g of high purity, white product was isolated (79% yield). m. p. [166-168C.] [H-NMR] (DMSO-d6) [5] ppm: 4. 58 (m, 2H) ; 4.38 (q, 2H); 4.24 (m, 2H); 1.43 (s, 9H); 1.32 (t, 3H).
1.98 g
With iodine; isopentyl nitrite; In dichloromethane; at 20℃; for 1.0h;
To a solution of iodine (3.330 g, 13.120 mmol) in DCM (35 ml) was added isoamyl nitrite (2.95 ml, 21.99 mmol) at rt. 5-Tert-butyl 1-ethyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-l,5- dicarboxylate (3.200 g, 10.81 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred at rt for 1 h. The resulting reaction mixture was poured into saturated aqueous Na2S2O3 solution (150 ml) and extracted with DCM (3 x 150 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) yielding 5-tert-butyl 1-ethyl 3-iodo-4,6- dihydropyrrolo[3,4-c]pyrazole-l,5-dicarboxylate (1.980 g, 4.86 mmol). LCMS: Method 1, 2.543 min, MS: ES+ 408.50
5-tertbutoxycarbonyl-1-ethoxycarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With isopentyl nitrite; In tetrahydrofuran; for 4.0h;Heating / reflux;
A solution of 3-amino-5-tert-butyloxycarbonyl-1-ethoxycarbonyl- -4, 6- dihydropyrrolo [3,4-c] pyrazole (0.4g, 1.35 mmol) in dry tetrahydrofurane [(10ML)] was added drop wise to a solution of isoamylnitrite (0. [32ML,] 2. [36MMOL)] in dry tetrahydrofurane (2ml) maintained at reflux. The resulting solution was stirred at reflux for 4 hours, and then cooled to room temperature. After removal of the solvent under vacuum, the crude material was purified by flash chromatography on silica gel using n- [HEXANE. ETHYL] acetate [90No.10 ]; 70-30. The title compound was obtained as a light yellow oil (200mg, y 53%). [H-NMR] (DMSO-d6) [8] ppm: 7.67 (s, 1H); 4.54 (m, 2H); 4.39 (q, 2H); 4.32 (m, [2H)] ; 1.43 (s, 9H); 1.31 (t, 3H).
5) 33.1 g (0.16 mol) of the general formula (14) was added to 200 mL of anhydrous ethanol,22.4 g (0.16 mol) of ethyl hydrazinecarboxylate hydrochloride was added in portions, and the reaction was carried out at 60 C for 4 to 5 hours. The reaction was monitored by TLC.The filtrate was concentrated under reduced pressure to give 40.3 g of a white solid of general formula (17).
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110K+ Compounds
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