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CAS No. : | 13138-76-6 | MDL No. : | MFCD03789112 |
Formula : | C7H8N2O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SEOKAHOXOYKYKS-UHFFFAOYSA-N |
M.W : | 184.15 g/mol | Pubchem ID : | 2759930 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.29 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 45.8 |
TPSA : | 77.05 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.94 cm/s |
Log Po/w (iLOGP) : | 1.79 |
Log Po/w (XLOGP3) : | 0.68 |
Log Po/w (WLOGP) : | 0.72 |
Log Po/w (MLOGP) : | -0.66 |
Log Po/w (SILICOS-IT) : | -1.45 |
Consensus Log Po/w : | 0.22 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.5 |
Solubility : | 5.87 mg/ml ; 0.0319 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.87 |
Solubility : | 2.46 mg/ml ; 0.0133 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.63 |
Solubility : | 43.4 mg/ml ; 0.236 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.2 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
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* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester With hydrogen In methanol for 1h; Stage #2: 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -20 - 20℃; for 0.5h; | Compound 2 (0.34 g, 1.85 mmol) in methanol (150 ml) and Pd/C (10%, 0.03 g) were stirred under H2 (1 atm) for 1 hr. The catalyst was removed (celite), and the solvent evaporated to dryness. Diisopropyl ethylamin (1 ml) in THF (5 ml) was added, the solution cooled TO-20 °C, and treated with a solution of the acid chloride of 1 (0. 31g, refluxed with thionyl chloride) in THF (5 ml). The mixture was allowed to warm to room temperature and stirred for a further 30 min. The solvent was evaporated to dryness, and water (5 ml) added. The solid was collected, and recrystallized by dissolving in hot DMF and precipitating with ethanol. Yield 0.46 g (82%). H NMR (DMSO): 8 10.23 (s, 1H, NH); 8.16 (d, 1H, J = 1.9 Hz); 7.52 (d, 1H, J = 2.0 Hz); 7.43 (d, 1H, J = 2.0 Hz); 6. 87 (d, 1H, J = 1. 9 Hz); 3.93 (s, 3H); 3.86 (s, 3H); 3.73 (s, 3H). |
With hydrogen; N-ethyl-N,N-diisopropylamine 1.) MeOH, 1 atm, 2.) THF, 3) THF, RT, 30 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With alkaline solution | |
95% | With methanol; sodium hydroxide In water at 60℃; | |
95% | With water; sodium hydroxide In methanol at 20 - 60℃; for 17h; |
94% | Stage #1: 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester With sodium hydroxide at 20℃; for 17h; Stage #2: With hydrogenchloride In water at 20℃; for 0.25h; | 4 Synthesis of 1 -methyl-4-nitro- 1H-pyrrole-2-carboxylic acid 4-Nitro-1-methyl-pyrrole-2-carboxylate methyl ester (5 g, 27.15 mmol) was suspended in ethanol (70 mL). Solution of NaOH (3.2 g, 80 mmol) in water (50 mL) wasadded and resulting mixture was stirred at room temperature for 17 hrs. The reaction mixture was evaporated to dryness. 6N HCl (13.5 mL, 81 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Obtained white solid product was filtered, washed with water and dried under reduced pressure. 1-Methyl-4-nitro-1H-pyrrole-2-carboxylic acid (4.36 g) was obtained with a yield of 94%. ‘H NMR (ö, DMSO-d6, ppm) 13.1 (bs, 1H,COOH), 7.24 (d, 1H, J = 2.1 Hz, H-5), 8.21 (d, 1H, J = 2.1 Hz, H-3), 3.90 (s, 3H, N-Me). |
92% | With sodium hydroxide Heating; | |
91% | With sodium hydroxide In tetrahydrofuran | |
91% | With water; sodium hydroxide In methanol at 20℃; for 2h; | |
88% | Stage #1: 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester With water; sodium hydroxide In tetrahydrofuran Stage #2: With phosphoric acid In water | 12 1 -Methyl-4-nitro- 1 H-pyrrole-2-carboxylic acid[256] Methyl 1 -methyl-4-nitro- lH-pyrrole-2-carboxylate (5.0 g, 27.17 mmol) in 120 ml of 1 : 1 THFZH2O was added 8 g of NaOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1 :1). The aqueous solution was adjusted to pH 3 ~4 with 20% H3PO4 and extracted with EtAc (4 x 60 ml). The organic solutions were combined, dried over MgSO4, filtered, evaporated and crystal]ized with ethanol/EtAc/Hexane to afford 4.06 g (88%) of the title product. 1H NMR (DMSO) 13.12 (s, IH), 8.21 (s, IH), 7.25 (s, IH), 3.91 (s, 3H); 13C NMR 160.97, 134.01, 129.16, 123.81, 111.38, 37.47; MS m/z- 169.1 (M-H). |
With sodium hydroxide In tetrahydrofuran; methanol | ||
With sodium hydroxide In tetrahydrofuran; methanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen In methanol for 3h; Ambient temperature; | |
100% | With hydrogen In N,N-dimethyl-formamide | |
100% | With palladium on carbon; hydrogen In methanol for 3h; |
62% | With palladium on activated charcoal; hydrogen at 20℃; | |
With hydrogen In ethanol at 50℃; for 12h; | ||
With hydrogen In tetrahydrofuran; methanol | ||
With hydrogen In ethyl acetate for 48h; | ||
With hydrogen In methanol; ethyl acetate at 20℃; for 16h; | ||
With hydrogen In N,N-dimethyl-formamide at 20℃; for 12h; | ||
With hydrogen In methanol at 20℃; for 3h; | ||
With hydrogen In N,N-dimethyl-formamide at 20℃; for 18h; | ||
With hydrogen In ethyl acetate at 20℃; | ||
With hydrogen In methanol at 20℃; for 2h; | ||
With hydrogen In ethyl acetate at 20℃; | ||
With hydrogen In methanol at 20℃; | ||
With hydrogen In ethyl acetate at 20℃; for 10h; | ||
With hydrogen for 2h; | ||
With hydrogen In ethyl acetate for 12h; | ||
With sodium tetrahydroborate In methanol; ethyl acetate at 0℃; | ||
With hydrogen In N,N-dimethyl-formamide for 1h; | ||
With hydrogen | ||
With hydrogen In methanol for 2h; | ||
With hydrogen In methanol for 24h; atmospheric pressure; | ||
With hydrogen In ethyl acetate for 4.5h; | ||
With hydrogen In ethyl acetate for 16h; | Methyl 1 -methyl-4-nitropyrrole-2- carboxylate 31 (6.0 g, 32.6 mmol) was dissolved in EtOAc (100 mL). A slurry of moist 10% Pd/C (600 mg) in EtOAc was added and the contents were stirred vigorously under H2 (70 psi) for 16 h. The reaction mixture was filtered through a bed of Celite. The Celite was washed with MeOH and the combined filtrate was evaporated under reduced pressure to furnish crude amine as dark oil. The crude oil, without any further purification, was taken up in CH3CN (60 mL). Contents were cooled to 0 °C and DIPEA (12 mL, 62.4 mmol) was added. A solution of l-methyl-2- trichloroacetylimidazole 24 (8.5 g, 31 mmol) in CH3CN (10 mL) was added and the reaction mixture was allowed to stir at ambient temperature for 14 h. Solvents were removed under reduced pressure and the solid obtained was washed with hexanes and filtered to afford 32. (8.0 g, 94 %). 1H-NMR (CDCl3) 09.08 (s, exch, IH, NH), 7.41 (s, IH, Py-C5H), 7.03 (s, IH, Im-C5H), 6.98 (s, IH, Im-C4H), 6.80 (s, IH, Py-C3H), 4.08 (s, 3H, CH3), 3.90 (s, 3H, CH3), 3.78 (s, 3H, OCH3). 13C-NMR (75 MHz, DMSO-d6) 6161.8 (+, s, CO), 157.1 (+, s, CO), 139.1 (+, s, Im-C2), 128.3 (-, d, Im- C4), 127.1 (-, d, Im-C5), 122.6 (+, s, Py-C2), 121.7 (-, d, Py-C5), 119.7 (+, s, Py-C4), 109.5 (-, d, Py-C3), 51.2 (-, q, OCH3), 37.9 (-, q, CH3), 35.5 (-, q, CH3). EI-HRMS: m/z calcd for C12H14N4O3 262.1066, found 262.1056 (M+, 100%), 174.0661 (20%), 109.0407 (40%). | |
With hydrogen In methanol; ethyl acetate for 14h; | Methyl 4-nitro-pyrrole-2- carboxylate 31 (3.8 g, 20.6 mmol) was dissolved in a mixture of MeOH-EtOAc (1 : 1, 150 mL). A slurry of moist 10% Pd/C in EtOAc was added and the contents were stirred vigorously under hydrogen (70 psi) for 14 h. The reaction mixture was filtered through a bed of Celite. The Celite was washed with MeOH and the filtrate was concentrated under reduced pressure to furnish crude amine as oil. The crude amine without any further purification was taken up in CH3CN (150 mL) and DIEA (5 mL). A solution of l-methyl-4-nitro-2-trichloroacetylimidazole 25 (5.4 g, 19.8 mmol) in CH3CN (20 mL) was added and the reaction mixture was allowed to stir at ambient temperature for 14 h, during which solid precipitated out. The reaction mixture was filtered to furnish 34 as yellow solid (4.8 g, 70.5 %). 1H-NMR (CDCl3) 68.96 (s, exch, IH, NH), 7.82 (s, IH, Im-CH), 7.37 (d, IH, J = 1.9 Hz, Py-CH), 6.86 (d, IH, J = 1.9 Hz, Py-CH), 4.19 (s, 3H, CH3), 3.92 (s, 3H, CH3), 3.82 (s, 3H, CH3), 13C-NMR (75 MHz, DMSO-d6) 6160.9 (+, s, CO), 154.9 (+, s, CO), 144.5 (+, s, Im-C4), 137.8 (+, s, Im-C2), 126.9 (-, d, Im-C5), 121.9 (+, s, Py-C2), 121.6 (-, d, Py-C5), 119.1 (+, s, Py-C4), 109.3 (-, d, Py-C3), 51.2 (-, q, OCH3), 36.8 (-, q, CH3), 36.5 (-, q, CH3). EI- HRMS: m/z calcd for Ci2H13N5O5 307.0917; found 307.0920 (M+, 100%), 180.0538 (88%), 149.0358 (42%). | |
With sodium tetrahydroborate; 5%-palladium/activated carbon In methanol; water; ethyl acetate at 0℃; | ||
With sodium tetrahydroborate; palladium 10% on activated carbon In methanol; water; ethyl acetate at 0 - 20℃; for 0.5h; | MeO-Py-Ind (15) A mixture of NaBH4 (92 mg, 2.44 mmol) in water (2ml) was added dropwise to a solution of MeO-Py-NO2 (9) (150 mg, 0.82 mmol) and Pd/C (10%) (30 mg) in EtOAc:MeOH (3:3) at 0 °C. The reaction mixture was allowed to warm up to rt and was stirred for 30 min. The catalyst was removed by vacuum filtration through Celite, and the solvent was evaporated to afford amine (14), which was used without further purification. A solution of 2-indole carboxylic acid (8) (120mg, 0.75mmol), PyBOP (429 mg, 0.83 mmol) and DIEA (261 ml, 1.5 mmol) in DCM (2 ml) was stirred at rt for 30 min. Next, a solution of amine (14) in DCM (2 ml) was added to the previous activated acid and was stirred at rt overnight. The reaction mixture was washed with HCl (1 M), extracted with DCM, washed with brine, dried over Na2SO4, then filtered and the solvent was evaporated in vacuo. A white solid was obtained in 90% yield. | |
With palladium 10% on activated carbon; hydrogen In methanol; water for 1h; Large scale; | ||
With palladium 10% on activated carbon; hydrogen In methanol for 2h; Autoclave; | Methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (42) 182 mg (0.99 mmol) methyl 1-methyl-4-nitro-1H-pyrrole-2-carboxylate (41) was dissolved in 10 mL methanol in an autoclave. The solution was purged with Ar, then 10 mg 10 % Pd/C was added. The mixture was stirred vigorously under H2 (1 bar) for 2 h. Pd/C was removed by filtration, methanol was removed under reduced pressure. 430 mg (0.5 mmol, 99%) brownish oil was obtained. The amine was not stable so we used it without further purification. | |
With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 80℃; | |
96% | With sodium hydride at 20℃; for 1h; | |
96% | Stage #1: methanol; 1-methyl-4-nitro-2-trichloroacetylpyrrole With sodium hydride at 20℃; for 1h; Stage #2: With sulfuric acid In water |
89% | With dmap | |
80% | at 20℃; for 0.5h; | Compound 23 (2.7 g,10 mmol) was dissolved in dry MeOH and a catalytic amount of NaH (100 mg) was added to the solution. After stirring the mixture for 30 min at ambient temperature, the solid present in the suspension was collected by filtration and recrystallized (1PrOH) to afford the title product (80% yield). HRMS: C7H8N2O4 184.0484 |
80% | With dmap at 20℃; for 72h; | |
80% | With dmap at 20℃; for 72h; | |
47% | With sodium methylate for 2h; Ambient temperature; | |
With dmap at 20℃; | ||
With sodium hydride at 20℃; for 2h; | 4 Synthesis of methyl 1 -methyl-4-nitro- 1 H-pyrrole-2-carboxylate A solution of 2,2,2-trichloro- 1 -(1 -methyl-4-nitro- 1 H-pyrrol-2-yl)ethanone (24 g, 87 mmol) in methanol (75 mL) was added dropwise to the suspension of NaH (300 mg) inmethanol (30 mL). The reaction mixture was stirred at room temperature for 2 hr, then the reaction was quenched by addition of concentrated sulfuric acid (0.75 mL). The reaction mixture was then heated to reflux and allowed to slowly cool to room temperature. Product crystallized from reaction mixture as white needles. Product was filtered and dried under vacuum. ‘H NMR (ö, DMSO-d6, ppm) 8.27 (bs, 1H, H-5), 7.31 (bs, 1H, H-3), 3.93, 3.80 (2s,3H ea, Me). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In acetone at 20℃; | |
72% | Stage #1: methyl 4-nitropyrrole-2-carboxylate With potassium In tetrahydrofuran for 1h; Heating; Stage #2: methyl iodide In tetrahydrofuran for 1h; Heating; | |
65% | Stage #1: methyl 4-nitropyrrole-2-carboxylate With tetra-(n-butyl)ammonium iodide; sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide Inert atmosphere; | Methyl 1-methyl-4-nitro-1H-pyrrole-2-carboxylate (41) General procedure: To the solution of 310 mg (1.82 mmol) methyl 4-nitro-1H-pyrrole-2-carboxylate (29)6 and 67 mg (0.18 mmo; 0.1 equiv.) tetrabutylammonium iodide in dry DMF (5 mL) 91 mg (2.28 mmol, 1.25 equiv.) 60 % NaH was added under argon at 0°C. After 10 minutes 227 µL (3.64 mmol, 2 ekv.) iodomethane was added and stirred overnight. Ethyl acetate was then added (100 mL), washed with water (2 × 10 mL) and brine (2 × 10 mL) and the organic phase was evaporated. The crude mixture was purified with flash column chromatography using a gradient of hexane/ethyl acetate = 6/1 to 2/1. 21 mg (65%) yellow solid product was obtained; 1H-NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 4.02 (s, 3H), 7. 45 (d, J = 2,0 Hz, 1H), 7.62 (d, J = 2,0 Hz, 1H) |
55% | With sodium hydride In N,N-dimethyl-formamide at 20℃; | |
26.b (b) (b) Preparation of methyl N-methyl-4-nitro-2-pyrrolecarboxylate Following the basic procedure of Example 25(d), by reacting 2.9 g (17 mmol) of methyl 4-nitro-2-pyrrolecarboxylate with 1.1 ml of iodomethane, 2.8 g (89%) of the expected compound of melting point 122°-124° C. were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid for 12h; Heating; | |
79% | With sulfuric acid for 24h; Heating / reflux; | A solution of H2S04 (0.4 ml) in MeOH (4 ml) was added to compound 1 (0.4 g, 2.35 mmol) and the mixture refluxed for 24 hr. Water was added and the mixture extracted with CHC13. The organic layer was dried (MGS04), and the solvent evaporated under vacuum. The residue was purified by flash chromatography (100% CH2C12) to yield the product as a crystalline solid. Yield 0.33 g (79%). LH NMR (DMSO): 8 7.57 (d, 1H, J = 2.1 Hz); 7.40 (d, 1H, J = 2.0 Hz); 3.99 (s, 3H) ; 3.86 (s, 3H, COOCH3). |
66% | With sulfuric acid for 24h; Heating / reflux; | A solution OF H2SO4 (0.8 mL) in MeOH (8 mL) was added to PY-1 (0.77 g, 4.53 mmol) and the mixture heated at reflux for 24 hr. Water was added and the mixture extracted with DCM. The organic solvent was dried using MGS04, and solvent evaporated under vacuum to yield the product as a crystalline solid. Yield 0.55 g, 66%). IH NMR (DMSO): 6 7.57 (d, 1H, J=2.1 Hz); 7.40 (d, 1H, J=2.0 Hz); 3.99 (s, 3H); 3.86 (s, 3H). |
39% | With sulfuric acid for 12h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H2 / Pd/C / dimethylformamide / 18 h / 20 °C 2: 444 mg / triethylamine / CH2Cl2; dimethylformamide | ||
Multi-step reaction with 2 steps 1: H2 2: 2.98 g / CH2Cl2 / 4 h / 20 °C | ||
Multi-step reaction with 2 steps 1: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 2: 85 percent / Et3N / dimethylformamide / 2 h / -5 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: H2 / Pd/C / dimethylformamide / 18 h / 20 °C 2: 444 mg / triethylamine / CH2Cl2; dimethylformamide 3: 96 percent / NaOH / ethanol / 1 h / Heating | ||
Multi-step reaction with 3 steps 1: H2 2: 2.98 g / CH2Cl2 / 4 h / 20 °C 3: 95 percent / aq. NaOH / ethanol / 20 °C | ||
Multi-step reaction with 3 steps 1: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 2: 85 percent / Et3N / dimethylformamide / 2 h / -5 - 20 °C 3: 96 percent / NaOH / ethanol; H2O / 1 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: NaBH4 / Pd/C / methanol; ethyl acetate / 0 °C 2: dimethylformamide 3: NaBH4 / Pd/C / methanol; ethyl acetate / 0 °C 4: EDCI; DMAP / dimethylformamide | ||
Multi-step reaction with 4 steps 1: H2 / Pd/C / dimethylformamide / 18 h / 20 °C 2: 2.15 g / triethylamine / CH2Cl2; tetrahydrofuran 3: H2 / Pd/C / dimethylformamide 4: 1.33 g / triethylamine / CH2Cl2 / pH 15 | ||
Multi-step reaction with 4 steps 1: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 2: 87 percent / Et3N / dimethylformamide / 2 h / -5 - 20 °C 3: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 4: 80 percent / Et3N / dimethylformamide / 2 h / -5 - 20 °C |
Multi-step reaction with 4 steps 1.1: sodium hydroxide / 17 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h 2.2: 18.5 h / Inert atmosphere 3.1: palladium 10% on activated carbon; hydrogen / ethyl acetate; methanol / 1551.49 Torr 4.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h / 20 °C 4.2: 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: NaOH / methanol | ||
Multi-step reaction with 5 steps 1: NaOH / methanol | ||
Multi-step reaction with 3 steps 1: NaOH / methanol |
Multi-step reaction with 5 steps 1: NaBH4 / Pd/C / methanol; ethyl acetate / 0 °C 2: dimethylformamide 3: NaBH4 / Pd/C / methanol; ethyl acetate / 0 °C 4: EDCI; DMAP / dimethylformamide 5: 95 percent / aq. NaOH | ||
Multi-step reaction with 5 steps 1: H2 / Pd/C / dimethylformamide / 18 h / 20 °C 2: 2.15 g / triethylamine / CH2Cl2; tetrahydrofuran 3: H2 / Pd/C / dimethylformamide 4: 1.33 g / triethylamine / CH2Cl2 / pH 15 5: 94 percent / NaOH / ethanol; H2O / 1 h / Heating | ||
Multi-step reaction with 5 steps 1: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 2: 87 percent / Et3N / dimethylformamide / 2 h / -5 - 20 °C 3: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 4: 80 percent / Et3N / dimethylformamide / 2 h / -5 - 20 °C 5: 94 percent / NaOH / ethanol; H2O / 1 h / Heating | ||
Multi-step reaction with 5 steps 1.1: sodium hydroxide / 17 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h 2.2: 18.5 h / Inert atmosphere 3.1: palladium 10% on activated carbon; hydrogen / ethyl acetate; methanol / 1551.49 Torr 4.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h / 20 °C 4.2: 24 h / 20 °C 5.1: sodium hydroxide; water / ethanol / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: NaBH4 / Pd/C / methanol; ethyl acetate / 0 °C 2: dimethylformamide | ||
Multi-step reaction with 2 steps 1: H2 / Pd/C / dimethylformamide / 18 h / 20 °C 2: 2.15 g / triethylamine / CH2Cl2; tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: H2 / Pd/C / methanol / 3 h / 20 °C / 760 Torr 2: 228 mg / Huenig's base / tetrahydrofuran / 0.5 h / 20 °C |
Multi-step reaction with 2 steps 1: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 2: 87 percent / Et3N / dimethylformamide / 2 h / -5 - 20 °C | ||
Multi-step reaction with 3 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: 1.) H2, 2.) Hunig's base / 10percent Pd/C / 1.) MeOH, 1 atm, 2.) THF, 3) THF, RT, 30 min | ||
Multi-step reaction with 2 steps 1: 95 percent / aq. alkaline solution | ||
Multi-step reaction with 2 steps 1.1: sodium hydroxide / 17 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h 2.2: 18.5 h / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: NaBH4 / Pd/C / methanol; ethyl acetate / 0 °C 2: dimethylformamide 3: NaBH4 / Pd/C / methanol; ethyl acetate / 0 °C | ||
Multi-step reaction with 3 steps 1: H2 / Pd/C / dimethylformamide / 18 h / 20 °C 2: 2.15 g / triethylamine / CH2Cl2; tetrahydrofuran 3: H2 / Pd/C / dimethylformamide | ||
Multi-step reaction with 3 steps 1: H2 / Pd/C / methanol / 3 h / 20 °C / 760 Torr 2: 228 mg / Huenig's base / tetrahydrofuran / 0.5 h / 20 °C 3: H2 / Pd/C / methanol |
Multi-step reaction with 3 steps 1: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 2: 87 percent / Et3N / dimethylformamide / 2 h / -5 - 20 °C 3: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr | ||
Multi-step reaction with 5 steps 1: H2 / Ni-raney / ethanol / 12 h / 50 °C 2: 84 percent / CH2Cl2 / 12 h / Heating 3: 93 percent / aq. NaOH / methanol / 18 h / Heating 4: dicyclohexylcarbodiimide, dimethylaminopyridine / CH2Cl2 / 4 h 5: TFA / CH2Cl2 / 1 h / Ambient temperature | ||
Multi-step reaction with 3 steps 1: H2 / Ni-raney / ethanol / 12 h / 50 °C 2: dicyclohexylcarbodiimide, dimethylaminopyridine / CH2Cl2 / 4 h 3: TFA / CH2Cl2 / 1 h / Ambient temperature | ||
Multi-step reaction with 3 steps 1.1: sodium hydroxide / 17 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h 2.2: 18.5 h / Inert atmosphere 3.1: palladium 10% on activated carbon; hydrogen / ethyl acetate; methanol / 1551.49 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H2 / 10 percent Pd/C / methanol / 20 °C 2: i-Pr2NEt / CH2Cl2 / 20 °C | ||
Multi-step reaction with 2 steps 1: H2 2: 81 percent / ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: H2 / 10 percent Pd/C / methanol / 20 °C 2: i-Pr2NEt / CH2Cl2 / 20 °C 3: H2 / 10 percent Pd/C / methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: H2 / 10 percent Pd/C / methanol / 20 °C 2: i-Pr2NEt / CH2Cl2 / 20 °C 3: H2 / 10 percent Pd/C / methanol / 20 °C 4: i-Pr2NEt / CH2Cl2 / 20 °C 5: NaBH4; Pd/C / methanol; ethyl acetate; H2O / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: H2 / 10 percent Pd/C / methanol / 20 °C 2: i-Pr2NEt / CH2Cl2 / 20 °C 3: H2 / 10 percent Pd/C / methanol / 20 °C 4: i-Pr2NEt / CH2Cl2 / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: H2 / 10 percent Pd/C / methanol / 20 °C 2: i-Pr2NEt / CH2Cl2 / 20 °C 3: H2 / 10 percent Pd/C / methanol / 20 °C 4: i-Pr2NEt / CH2Cl2 / 20 °C 5: NaBH4; Pd/C / methanol; ethyl acetate; H2O / 20 °C 6: i-Pr2NEt / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: H2 / 10 percent Pd/C / methanol / 20 °C 2: i-Pr2NEt / CH2Cl2 / 20 °C 3: H2 / 10 percent Pd/C / methanol / 20 °C 4: i-Pr2NEt / CH2Cl2 / 20 °C 5: NaBH4; Pd/C / methanol; ethyl acetate; H2O / 20 °C 6: i-Pr2NEt / 20 °C 7: 79 percent / aq. NaOH / 48 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: H2 / Pd/C / dimethylformamide / 18 h / 20 °C 2: 2.15 g / triethylamine / CH2Cl2; tetrahydrofuran 3: H2 / Pd/C / dimethylformamide 4: triethylamine / tetrahydrofuran; CH2Cl2 | ||
Multi-step reaction with 4 steps 1: H2 / Pd/C / methanol / 3 h / 20 °C / 760 Torr 2: 228 mg / Huenig's base / tetrahydrofuran / 0.5 h / 20 °C 3: H2 / Pd/C / methanol 4: 360 mg / Huenig's base / tetrahydrofuran / 0.5 h / 20 °C | ||
Multi-step reaction with 4 steps 1: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 2: 87 percent / Et3N / dimethylformamide / 2 h / -5 - 20 °C 3: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 4: Et3N / dimethylformamide / 2 h / -5 - 20 °C |
Multi-step reaction with 2 steps 1.1: sodium hydroxide / 17 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h / 20 °C 2.2: 24 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: sodium hydroxide / 17 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h 2.2: 18.5 h / Inert atmosphere 3.1: palladium 10% on activated carbon; hydrogen / ethyl acetate; methanol / 1551.49 Torr 4.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h / 20 °C 4.2: 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: H2 / Pd/C / dimethylformamide / 18 h / 20 °C 2: 2.15 g / triethylamine / CH2Cl2; tetrahydrofuran 3: H2 / Pd/C / dimethylformamide 4: triethylamine / tetrahydrofuran; CH2Cl2 5: H2 / Pd/C / dimethylformamide / 18 h / 20 °C / 760 Torr 6: 840 mg / triethylamine / tetrahydrofuran; CH2Cl2 | ||
Multi-step reaction with 6 steps 1: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 2: 87 percent / Et3N / dimethylformamide / 2 h / -5 - 20 °C 3: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 4: Et3N / dimethylformamide / 2 h / -5 - 20 °C 5: H2 / Pd/C / dimethylformamide / 12 h / 20 °C / 760 Torr 6: Et3N / dimethylformamide / 2 h / -5 - 20 °C | ||
Multi-step reaction with 3 steps 1: palladium on activated charcoal; hydrogen / ethyl acetate 2: palladium on activated charcoal; hydrogen / ethyl acetate 3: palladium on activated charcoal; hydrogen / ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: H2 / Pd/C / methanol / 3 h / 20 °C / 760 Torr 2: 228 mg / Huenig's base / tetrahydrofuran / 0.5 h / 20 °C 3: 86 percent / KOH / methanol / 12 h / Heating | ||
Multi-step reaction with 4 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: 1.) H2, 2.) Hunig's base / 10percent Pd/C / 1.) MeOH, 1 atm, 2.) THF, 3) THF, RT, 30 min 4: 95 percent / NaOH / H2O; ethanol / Heating | ||
Multi-step reaction with 3 steps 1: 95 percent / aq. alkaline solution 3: aq. NaOH / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: H2 / Pd/C / dimethylformamide / 1 h / 25858.1 Torr 2.1: DCC; HOBt / dimethylformamide / 1.5 h / 20 °C 2.2: dimethylformamide / 37 - 55 °C 3.1: NaOMe-MeOH / 1.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: H2 / Pd/C / dimethylformamide / 1 h / 25858.1 Torr 2.1: DCC; HOBt / dimethylformamide / 1.5 h / 20 °C 2.2: dimethylformamide / 37 - 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1.2 kg / diethyl ether / 3 h 2: HNO3, Ac2O / -40 - 20 °C 3: 47 percent / NaOMe / 2 h / Ambient temperature | ||
Multi-step reaction with 3 steps 1: diethyl ether 2: nitric acid; acetic anhydride / isopropyl alcohol / -40 °C 3: 0.5 h | ||
Multi-step reaction with 3 steps 1: dichloromethane / 24 h / 20 °C 2: acetic anhydride; nitric acid / 2.5 h / -40 - 20 °C 3: sodium hydride / 2 h / 20 °C |
Multi-step reaction with 3 steps 1: diethyl ether / 0 - 20 °C / Inert atmosphere 2: acetic anhydride; nitric acid / -40 - 20 °C / Inert atmosphere 3: dmap / 72 h / 20 °C | ||
Multi-step reaction with 3 steps 1: diethyl ether / 17 h / 0 - 20 °C / Inert atmosphere 2: acetic anhydride; nitric acid / 16.5 h / -40 - 20 °C 3: dmap / 72 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: HNO3, Ac2O / -40 - 20 °C 2: 47 percent / NaOMe / 2 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: nitric acid; acetic anhydride / isopropyl alcohol / -40 °C 2: 0.5 h | ||
Multi-step reaction with 2 steps 1: acetic anhydride; nitric acid / 2.5 h / -40 - 20 °C 2: sodium hydride / 2 h / 20 °C |
Multi-step reaction with 2 steps 1: acetic anhydride; nitric acid / -40 - 20 °C / Inert atmosphere 2: dmap / 72 h / 20 °C | ||
Multi-step reaction with 2 steps 1: acetic anhydride; nitric acid / 16.5 h / -40 - 20 °C 2: dmap / 72 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H2 / 10percent Pd/C / methanol; tetrahydrofuran / 760 Torr 2: EDCI / tetrahydrofuran / 4 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature 2: 1.) 2 M aq. NaOH / 1.) MeOH, 0 deg C, 6 h, 2.) MeOH, ether, RT, 30 min | ||
Multi-step reaction with 7 steps 1: H2 / Ni-raney / ethanol / 12 h / 50 °C 2: 84 percent / CH2Cl2 / 12 h / Heating 3: 93 percent / aq. NaOH / methanol / 18 h / Heating 4: 1.) aq. Cs2CO2 / 1) H2O, EtOH; 2) DMF, 40 deg C, overnight 5: TFA / CH2Cl2 / 1 h 6: 1.) dicyclohexylcarbodiimide, HOBt, 2.) TEA / 1) CH2Cl2, 1 h; 2) CH2Cl2, 2 h, 0 deg C, 20 deg C (15 h) 7: 95 percent / H2 / Pd/C / ethanol / 12 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature 2: 1.) 2 M aq. NaOH / 1.) MeOH, 0 deg C, 6 h, 2.) MeOH, ether, RT, 30 min 3: 67 percent / EDCl / dimethylformamide / 1 h 4: dimethylformamide / 4 h / 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature 2: 1.) 2 M aq. NaOH / 1.) MeOH, 0 deg C, 6 h, 2.) MeOH, ether, RT, 30 min 3: 67 percent / EDCl / dimethylformamide / 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature 2: 1.) 2 M aq. NaOH / 1.) MeOH, 0 deg C, 6 h, 2.) MeOH, ether, RT, 30 min 3: 67 percent / EDCl / dimethylformamide / 1 h 4: dimethylformamide / 4 h / 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature 2: 1.) 2 M aq. NaOH / 1.) MeOH, 0 deg C, 6 h, 2.) MeOH, ether, RT, 30 min 3: 67 percent / EDCl / dimethylformamide / 1 h 4: dimethylformamide / 4 h / 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature 2: 1.) 2 M aq. NaOH / 1.) MeOH, 0 deg C, 6 h, 2.) MeOH, ether, RT, 30 min 3: 67 percent / EDCl / dimethylformamide / 1 h 4: dimethylformamide / 4 h / 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 100 percent / H2 / 10percent Pd/C / methanol / 3 h / Ambient temperature 2: 1.) 2 M aq. NaOH / 1.) MeOH, 0 deg C, 6 h, 2.) MeOH, ether, RT, 30 min 3: 67 percent / EDCl / dimethylformamide / 1 h 4: dimethylformamide / 4 h / 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 4: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C 5: 76 percent / H2 / 10percent Pd/C / methanol / 3 h / 40 °C | ||
Multi-step reaction with 7 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: H2 / 10percent Pd/C / methanol 5: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 6: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C 7: 76 percent / H2 / 10percent Pd/C / methanol / 3 h / 40 °C | ||
Multi-step reaction with 7 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: 1.) H2, 2.) HCl / 10percent Pd/C / 1.) methanol, 40 deg C, 1 atm, 2.) isopropanol, -30 deg C 5: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 6: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C 7: 76 percent / H2 / 10percent Pd/C / methanol / 3 h / 40 °C |
Multi-step reaction with 5 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 4: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C 5: 76 percent / H2 / 10percent Pd/C / methanol / 3 h / 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 4: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C | ||
Multi-step reaction with 6 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: H2 / 10percent Pd/C / methanol 5: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 6: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C | ||
Multi-step reaction with 6 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: 1.) H2, 2.) HCl / 10percent Pd/C / 1.) methanol, 40 deg C, 1 atm, 2.) isopropanol, -30 deg C 5: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 6: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C |
Multi-step reaction with 4 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 4: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C | ||
Multi-step reaction with 5 steps 1: 95 percent / aq. alkaline solution 3: aq. NaOH / ethanol 4: 97 percent / benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), Et3N / dimethylformamide / 1.5 h / Ambient temperature 5: 1.) HCl, 2.) NH3 / 1.) EtOH, 2.) EtOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 4: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr 5: 52 percent / DCC / dimethylsulfoxide / 2 h / Ambient temperature 6: 1.) HCl, 2.) NH3 / 1.) EtOH, RT, 2 h, 2.) EtOH, RT, 1 h | ||
Multi-step reaction with 8 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: H2 / 10percent Pd/C / methanol 5: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 6: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr 7: 52 percent / DCC / dimethylsulfoxide / 2 h / Ambient temperature 8: 1.) HCl, 2.) NH3 / 1.) EtOH, RT, 2 h, 2.) EtOH, RT, 1 h | ||
Multi-step reaction with 8 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: 1.) H2, 2.) HCl / 10percent Pd/C / 1.) methanol, 40 deg C, 1 atm, 2.) isopropanol, -30 deg C 5: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 6: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr 7: 52 percent / DCC / dimethylsulfoxide / 2 h / Ambient temperature 8: 1.) HCl, 2.) NH3 / 1.) EtOH, RT, 2 h, 2.) EtOH, RT, 1 h |
Multi-step reaction with 6 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 4: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr 5: 52 percent / DCC / dimethylsulfoxide / 2 h / Ambient temperature 6: 1.) HCl, 2.) NH3 / 1.) EtOH, RT, 2 h, 2.) EtOH, RT, 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 4: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr | ||
Multi-step reaction with 6 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: H2 / 10percent Pd/C / methanol 5: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 6: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr | ||
Multi-step reaction with 6 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: 1.) H2, 2.) HCl / 10percent Pd/C / 1.) methanol, 40 deg C, 1 atm, 2.) isopropanol, -30 deg C 5: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 6: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr |
Multi-step reaction with 4 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 4: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature | ||
Multi-step reaction with 5 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: H2 / 10percent Pd/C / methanol 5: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature | ||
Multi-step reaction with 5 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: 1.) H2, 2.) HCl / 10percent Pd/C / 1.) methanol, 40 deg C, 1 atm, 2.) isopropanol, -30 deg C 5: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature |
Multi-step reaction with 3 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature | ||
Multi-step reaction with 4 steps 1: 95 percent / aq. alkaline solution 3: aq. NaOH / ethanol 4: 97 percent / benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), Et3N / dimethylformamide / 1.5 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 4: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C 5: 76 percent / H2 / 10percent Pd/C / methanol / 3 h / 40 °C 6: tetrahydrofuran; methanol / 0.25 h / -40 °C | ||
Multi-step reaction with 8 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: H2 / 10percent Pd/C / methanol 5: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 6: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C 7: 76 percent / H2 / 10percent Pd/C / methanol / 3 h / 40 °C 8: tetrahydrofuran; methanol / 0.25 h / -40 °C | ||
Multi-step reaction with 8 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: 1.) H2, 2.) HCl / 10percent Pd/C / 1.) methanol, 40 deg C, 1 atm, 2.) isopropanol, -30 deg C 5: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 6: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C 7: 76 percent / H2 / 10percent Pd/C / methanol / 3 h / 40 °C 8: tetrahydrofuran; methanol / 0.25 h / -40 °C |
Multi-step reaction with 6 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 4: 1.) HCl, 2.) NH3 / 1.) EtOH, room temp., 1.5 h, 2.) EtOH, MeOH, 55 deg C 5: 76 percent / H2 / 10percent Pd/C / methanol / 3 h / 40 °C 6: tetrahydrofuran; methanol / 0.25 h / -40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 4: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr 5: 52 percent / DCC / dimethylsulfoxide / 2 h / Ambient temperature | ||
Multi-step reaction with 7 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: H2 / 10percent Pd/C / methanol 5: Hunig's base / tetrahydrofuran / 0.5 h / Ambient temperature 6: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr 7: 52 percent / DCC / dimethylsulfoxide / 2 h / Ambient temperature | ||
Multi-step reaction with 7 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran / -20 - 20 °C 4: 1.) H2, 2.) HCl / 10percent Pd/C / 1.) methanol, 40 deg C, 1 atm, 2.) isopropanol, -30 deg C 5: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 6: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr 7: 52 percent / DCC / dimethylsulfoxide / 2 h / Ambient temperature |
Multi-step reaction with 5 steps 1: 92 percent / aq. NaOH / Heating 2: SOCl2 / tetrahydrofuran / 0.08 h / Heating 3: Hunig's base / tetrahydrofuran; acetonitrile / 0.5 h / Ambient temperature 4: 70 percent / H2 / 10percent Pd/C / dimethylformamide; methanol / 760 Torr 5: 52 percent / DCC / dimethylsulfoxide / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: H2 / Ni-raney / ethanol / 12 h / 50 °C 2: 84 percent / CH2Cl2 / 12 h / Heating 3: 93 percent / aq. NaOH / methanol / 18 h / Heating 4: 1.) aq. Cs2CO2 / 1) H2O, EtOH; 2) DMF, 40 deg C, overnight 5: TFA / CH2Cl2 / 1 h 6: 1.) dicyclohexylcarbodiimide, HOBt, 2.) TEA / 1) CH2Cl2, 1 h; 2) CH2Cl2, 2 h, 0 deg C, 20 deg C (15 h) 7: 95 percent / H2 / Pd/C / ethanol / 12 h 8: 59 percent / TFA, EDC / dimethylformamide / Ambient temperature 9: 77 percent / H2 / Pd/C / dimethylformamide / 6 h / Ambient temperature | ||
Multi-step reaction with 9 steps 1: H2 / Ni-raney / ethanol / 12 h / 50 °C 2: 84 percent / CH2Cl2 / 12 h / Heating 3: 93 percent / aq. NaOH / methanol / 18 h / Heating 4: 1.) aq. Cs2CO2 / 1) H2O, EtOH; 2) DMF, 40 deg C, overnight 5: TFA / CH2Cl2 / 1 h 6: 87 percent / dicyclohexylcarbodiimide, dimethylaminopyridine / CH2Cl2 / 4 h 7: TFA / CH2Cl2 / 1 h / Ambient temperature 8: 59 percent / TFA, EDC / dimethylformamide / Ambient temperature 9: 77 percent / H2 / Pd/C / dimethylformamide / 6 h / Ambient temperature | ||
Multi-step reaction with 7 steps 1: H2 / Ni-raney / ethanol / 12 h / 50 °C 2: 84 percent / CH2Cl2 / 12 h / Heating 3: 93 percent / aq. NaOH / methanol / 18 h / Heating 4: 87 percent / dicyclohexylcarbodiimide, dimethylaminopyridine / CH2Cl2 / 4 h 5: TFA / CH2Cl2 / 1 h / Ambient temperature 6: 59 percent / TFA, EDC / dimethylformamide / Ambient temperature 7: 77 percent / H2 / Pd/C / dimethylformamide / 6 h / Ambient temperature |
Multi-step reaction with 5 steps 1.1: sodium hydroxide / 17 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h / 20 °C 2.2: 24 h / 20 °C 3.1: sodium hydroxide; water / ethanol / 15 h / 60 - 65 °C 4.1: palladium 10% on activated carbon; hydrogen; sodium carbonate / water; N,N-dimethyl-formamide / 1034.32 Torr 5.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.33 h / 20 °C 5.2: 0.5 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: sodium hydroxide / 17 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h 2.2: 18.5 h / Inert atmosphere 3.1: palladium 10% on activated carbon; hydrogen / ethyl acetate; methanol / 1551.49 Torr 4.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.33 h / 20 °C 4.2: 24 h / 20 °C 5.1: sodium hydroxide; water / ethanol / 15 h / 60 - 65 °C 6.1: palladium 10% on activated carbon; hydrogen; sodium carbonate / water; N,N-dimethyl-formamide / 1034.32 Torr 7.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.33 h / 20 °C 7.2: 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 1-methyl-4-nitro-2-trichloroacetylpyrrole With sodium methylate In methanol at 20℃; for 0.5h; Stage #2: With sulfuric acid In methanol Heating / reflux; | 4 Synthesis of 1-methyl-1H-pyrrolO[3,2-b]pyridine-2-carboxylic acid; methyl 1-methyl-4-nitropyrrole-2-carboxylate To a solution of 4-nitro-2-(trichloroacetyl)-1-methylpyrrole (48.6 g, 179.0 MMOL) in methanol (130 mL) was added NaOCH3 (100 MG, 1.85 MMOL) at room temperature. After exotherm ceased in 30 min, 98% H2SO4 (0.85 mL) and methanol (200 mL) were added.The mixture was heated to reflux until all the solid dissolved, then cooled to room temperature. The solid was collected by filtration and dried in vacuo to afford 30.34 g (92%) as a white SOLID. 1H NMR (300 MHz, CDCI3) # 7.60 (d, J=1.8 Hz, 1 H), 7.41 (d, J=1.8 Hz, 1H), 3.99 (s, 3H), 3.86 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.99% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In palladium-carbon; water; N,N-dimethyl-formamide | 2 (4-1) Peptide Formation Step 2: Example 1 of Peptide Bond Formation To a solution of 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester (65.68 mg, 0.3567 mmol) in EA (10 ml) was added 10% Pd/C (10 mg). The reaction solution was stirred for 10 hours at room temperature under hydrogen atmosphere to reduce a nitro group (NO2) into an amino group (NH2), whereby a pyrrole-type amino acid was obtained. 10% Pd/C was filtered out by celite 545 and the filtrate was washed with EA and methanol. 1-Methyl-4-[2-(4-trifluoromethyl-benzenesulfonyl)-ethoxycarbonylamino]-1H-pyrrole-2-carboxylic acid (49.98 mg, 0.1189 mmol) dissolved in a solvent mixture of anhydrous DMF (6 ml) and DCM (2 ml) was added thereto, TFFH (94.21 mg, 0.3567 mmol), HOBt (64.73 mg, 0.4756 mmol) and DIEA (82.84 ml, 0.4748 mmol) were also added thereto, and the reaction solution was stirred for 8 hours at room temperature. Distilled water was added to the reaction solution, which was then extracted with diethyl ether. The organic layer was dried over anhydrous MgSO4 and concentrated. The concentrate was purified by silica gel column chromatography (EA/n-hexane=3/1, v/v) to give 1-methyl-4-({1-methyl-4-[2-(4-trifluoromethyl-benzene-sulfonyl)-ethoxycarbonylamino]-1H-pyrrole-2-carbonyl}-amino)-1H-pyrrole-2-carboxylic acid methyl ester (41.70 mg, 62.99%) of a pale yellow solid. TLC (EA/n-hexane=3/1, v/v) Rf=0.43 1H NMR (DMSO-d6+CDCl3) δ 9.87 (s, 1H), 8.34 (s, 1H), 8.15 (d, J=8.1 Hz, 2H), 8.03 (d, J=8.1 Hz, 2H), 7.45 (d, J=1.8 Hz, 1H), 6.89 (d, J=1.5 Hz, 1H), 6.84 (s, 1H), 6.79 (s, 1H), 4.36 (bt, 2H), 3.84 (m, 8H), 3.73 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.42% | With dmap; benzotriazol-1-ol In palladium-carbon; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran | 2.1 (1) (1) Capping Step After 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester (1.17 g, 6.35 mmol) was dissolved in EA (20 ml), 10% Pd/C (50 mg, catalytic weight) was added thereto. The mixture was stirred for 1 hour at room temperature under hydrogen atmosphere to reduce a nitro group (NO2) into an amino group (NH2), whereby a pyrrole-type amino acid was obtained. 10% Pd/C was filtered out by celite 545 filter, and the filtrate was washed with EA and MeOH and concentrated under vacuum. To the residue were added carbonic acid 4-nitro-phenyl ester 2-(4-trifluoromethyl-phenylsulfanyl)-ethyl ester (2.23 g, 5.76 mmol) dissolved in anhydrous DCM (30 ml), DIEA (2.01 μm, 11.56 mmol), DMAP (1.41 g, 11.56 mmol), and HOBt (1.77 g, 11.56 mmol), and the mixture was stirred for 12 hours at room temperature. The reaction was stopped by adding water and the reaction mixture was extracted with DCM. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel column chromatography (EA/n-hexane=1/3, v/v) to give methyl 1-methyl-4-[2-(4-trifluoromethylphenylsulfanyl)-ethoxycarbonylamino]-1H-pyrrole-2-carboxylate (1.98 g, 85.42%) of a pale yellow solid. TLC (EA/n-hexane=1/3; v/v) Rf: 0.13 1H NMR (CDCl3) δ 7.54 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.1 Hz, 2H), 7.05 (s, 1H), 6.65 (s, 1H), 6.39 (brs, 1H), 4.33 (t, 2H), 3.88(s, 3H), 3.80 (s, 3H), 3.26 (t, 2H) 13C NMR (CDCl3) 161.35, 153.24, 140.79, 129.37, 128.40, 127.97, 127.65, 127.53, 127.10, 125.77, 125.73, 125.67, 125.62, 122.16, 121.33, 119.97, 118.56, 108.26, 63.00, 51.01, 36.61, 31.22 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In phosphorus pentaoxide; ethanol; ethyl acetate; N,N-dimethyl-formamide | 2.A 1H-Indole-2,5-dicarboxylic acid bis-[5-(2-amino-ethylcarbamoyl)-1-methyl-1H-pyrrol-3-yl/-amide} 11 Step A: 4-({1-[2-(5-methoxycarbonyl-1methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl]-amino)-1-methyl-1H-pyrrole-2carboxylic acid methyl ester 8 To a stirred solution of methyl 4-nitro-1-methyl-1H-pyrrole-2-carboxylate (967 mg, 5.25 mmole) in a mixture of AcOEt/EtOH (3/2) (50 ml) was added 10% Pd/C (Degussa type, Aldrich) (0.2g). The flask was evacuated and then flushed 3 times with hydrogen and finally filled with hydrogen at 40 to 50 psi. The resultant suspension was stirred vigrously at 23° C. for 1 hour. The suspended material was filtered off through a pad of Celite in a Buchner funnel and then the funnel was rinsed several times with a small portion of AcOEt and EtOH. The combined filtrate and washings was evaporated in vacuo to dryness. The resulted methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate was used for the next step without purification. A solution of compound 2 (1.13, 2.1 mmole) and freshly prepared (as described above) methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate in dry DMF (10.0 ml) was kept at ambient temperature for 48 hours and evaporated. The residue was re-precipitated from DMF (10 ml)-0.01 M HCl (100 ml). The precipitate was collected on the filter, washed with water (3*5 ml) and ether (2*3 ml) and dried in vacuo over phosphorus pentoxide to give 4-({1-[2-(5-methoxycarbonyl-1methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2carboxylic acid methyl ester 8 with quantitative yield. MS: 478.14 (M+H). 1H-NMR (DMSO-d6): δ11.96 (s, 1H, H-1, indole); 10.43,10.23 (s,s, 1H,1H, -C(=O)); 8.29 (m, 1H, H-6, indole); 7.50 (m, 3H, H-7, indole; H-3 or H-5, Py1,Py2); 7.37 (s, 1H, H-3, indole); 6.95 (m, 2H, H-3 or H-5, Py1,Py2); 3.86,3.85 (s, 6H, N3, Py1,Py2); 3.74,3.73 (s, 6H, OCH3, Py1,Py2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In phosphorus pentaoxide; ethanol; ethyl acetate; N,N-dimethyl-formamide | 2.A Synthesis of 1H-indole-2,5-dicarboxylic acid bis-[5-(2-amino-ethylcarhamoyl)-1-methyl-1H-pyrrol-3-yl]-amide} (A) 4-({1-[2-(5-methoxycarbonyl-1methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2carboxylic acid methyl ester, 8 To a stirred solution of compound methyl 4-nitro-1-methyl-1H-pyrrole-2-carboxylate (967 mg, 5.25 mmole) in a mixture of AcOEt/EtOH (3/2) (50 ml) was added 10% Pd/C (Degussa type, Aldrich) (0.2 g). The flask was evacuated and then flushed 3 times with hydrogen and finally filled with hydrogen at 40 to 50 psi. The resultant suspension was stirred vigrously at 23° C. for 1 hour. The suspended material was filtered off through a pad of Celite in a Buchner funnel and then the funnel was rinsed several times with a small portion of AcOEt and EtOH. The combined filtrate and washings was evaporated in vacuo to dryness. The resulted methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate was used for the next step without purification. A solution of compound 7 (1.13, 2.1 mmole) and freshly prepared (as described above) methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate in dry DMF (10.0 ml) was kept at ambient temperature for 48 hours and evaporated. The residue was re-precipitated from DMF (10 ml)-0.01 M HCl (100 ml). The precipitate was collected on the filter, washed with water (3*5 ml) end ether (2*3 ml) and dried in vacuo over phosphorus pentoxide to give 4-({1-[2-(5-methoxycarbonyl-1methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2carboxylic acid methyl ester 8 with quantitative yield. MS: 478.14 (M+H). 1-NMR (DMSO-d6): 11.96 (s, 1H, H-1, indole); 10.43&10.23 (s&s, 1H&1H, -C(=O)NH); 8.29 (m, 1H, H-6, indole); 7.50 (m, 3H, H-7, indole; H-3 or H-5, Py1&Py2); 7.37 (s, 1H, H-3, indole); 6.95 (m, 2H, H-3 or H-5, Py1&Py2); 3.86&3.85 (s, 6H, NCH3, Py1&Py2); 3.74&3.73 (s, 6H, OCH3, Py1&Py2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate | 1 Preparation of Methyl 4-amino-1-methyl-pyrrole-2-carboxylate hydrochloride (7) Preparation of Methyl 4-amino-1-methyl-pyrrole-2-carboxylate hydrochloride (7) Recrystallized methyl 1-methyl-4-nitropyrrole-2-carboxylate 6 (40 g, 0.22 mol) was dissolved in 900 ml ethyl acetate. A slurry of 10 g of 10% Pd/C in 100 ml ethyl acetate was added and the mixture stirred under a slight positive pressure of hydrogen (about 1.1 ATM) for 48 hours. The Pd/C was removed by filtration through Celite, washed with 50 ml ethyl acetate, and the volume of the mixture was reduced to about 200 ml. 700 ml of ethyl ether was added and HCl gas gently bubbled through the mixture while maintaining a temperature below 20° C. The precipitated amine hydrochloride was then collected after storage at -20° C. for 40 hours to yield (38 g, 91%) of a very white powder. TLC (ethyl acetate) Rf amine (0.6), Rf salt (0.0); 1 H NMR (DMSO-d6) δ 10.23 (br s, 3H), 7.24 (d, 1H, J=1.9 Hz), 6.79 (d, 1H, J=2.0 Hz), 3.83 (s, 3H), 3.72 (s, 3H); 13 C NMR (DMSO-d6) δ 160.8, 124.3, 121.2, 113.4, 112.0, 51.8, 37.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.2% | Stage #1: 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester With ammonium formate In ethyl acetate for 2h; Heating / reflux; Stage #2: malonaldehydebis(dimethylacetal) With hydrogenchloride In water for 16h; Heating / reflux; | 4 Synthesis of 1-methyl-1H-pyrrolO[3,2-b]pyridine-2-carboxylic acid; 2-methoxycarbonyl-1-methylpyrrolO[3,2-b]pyridine A SOLUTION of methyl 1-methyl-4-nitropyrrole-2-carboxylate (10.02 g, 54.4 MMOL) and HCO2NH4 (17.2 g, 272.0 MMOL) in ethyl acetate (250 mL) was added 20% Pd (OH) 2/C. The mixture was heated to reflux for 2 h, then the catalyst was removed by filtration.The filtrate was EVAPORATED IN VACUO, then MALONALDEHYDE bis (dimethyl acetal) (26.8 g, 163.2 MMOL) and concentrated HCI (5 mL) were added, and the mixture was heated to reflux for 16 hours. After evaporation of the METHANOL IN VACUO, a saturated aqueous solution of NA2CO3 (150 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined extracts were washed with saturated NaCl (150 mL), dried over NA2SO4, concentrated, and purified by chromatography with hexane-acetone (3: 1) to afford 2.81 g (27.2%) of the desired product as a yellow SOLID. 1H NMR (300 MHz, CDCl3) 6 8.50 (dd, J=4.5 Hz, J=1.2 Hz, 1H), 7.61 (dd, J=5.5 Hz, J=1.2 Hz, 1H), 7.37 (s, 1H), 7.17 (dd, J=8.55 Hz, J=4.5 Hz, 1 H), 4.00 (s, 3H), 3.89 (s, 3H) ; 13C NMR (75 MHz, CDCI3) # 162. 2,145. 0,143. 4,132. 6,130. 0,117. 7,110. 1,51. 8,31. 5. Anal.Calc'd. for C10H10N2O2: C, 63.15 ; H, 5.30 ; N, 14.73. Found: C, 63.21 ; H, 5.30 ; N, 14.63. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester With hydrogen In methanol for 1h; Stage #2: 1-Methyl-2-pyrrolecarboxylic acid With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In DMF (N,N-dimethyl-formamide) for 1h; | NO2PYCOOCH3 (0.2 g, 1.086 mmol) in MeOH (60 mL) and Pd/C (10%, 0.04 g) were stirred under Ha (latm) for 1 hr (TLC- (Silica Gel 60 F254 precoated plated MERCK) 5% MeOH in DCM). The catalyst was removed using celite, DMF (3 mL) was added and MeOH was evaporated. L-METHYLPYRROLE-2-CARBOXYLIC acid (0.162 g, 1.3 mmol) was added followed by HOBT (0.22 g, 1.63 mmol), TBTU (0.524 g, 1.63 mmol), ET3N (0.76 mL, 5.42 mmol) and the solution stirred for 1 hr. DMF was evaporated under pressure and product was purified by column chromatography (5% MeOH/DCM) affording the product as a creamy yellow solid. Yield (0.4 g). 1H NMR (DMSO): 6 9.6 (bs, 1H, NH), 7.98 (s, 2H), 7.88 (d, 1H, J=2. 1 Hz), 7.34 (d, 1H, J=2 Hz), 6.93 (bs, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.79 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester With hydrogen In methanol for 1h; Stage #2: 1-methyl-4-[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1H-pyrrole-2-carboxylic acid With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In DMF (N,N-dimethyl-formamide) for 1h; | N02PYCOOCH3 (0.116 g, 0.63 mmol) in MeOH (50 mL) and Pd/C (10%, 0.04 g) were stirred under H2 (1 atm) for 1 hr ( (SILICA Gel 60 F254 precoated plated Merck)-5% MEOH/DCM). The catalyst was filtered using celite, DMF (4ml) was added, and solvent evaporated. PyPyCOOH (0.1 g, 0.42 mmol) was added followed by HOBT (0.09 g, 0.69 MMOL), TBTU (0.22 g, 0.69 mmol), Et3N (0.6 mL, 5.1 mmol) and the solution was stirred for LHR. The solvent was evaporated and the residue was purified by column chromatography (5% MeOH/DCM). Yield (0 : 21 g, 84%). IH NMR (CD30D) : 6 8.0 (s, 1H), 7.35 (bs, 1H), 7.2 (bs, 1H), 6.9 (bs, 1H), 6. 85 (bs, 1H), 6.1 (bs, 1H), 5. 5 (bs, 1H), 3.9 (s, 6H), 3.8 (s, 3H), 3.4 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; hydrogen In tetrahydrofuran; water for 5h; | 12 Methyl 1 -methyl-4-( 1 -methyl-4-nitro- 1 H-pyrrole-2-carboxamido)- 1 H-pyrrole-2-carboxylate[257] In a hydrogenation bottle was added methyl 1 -methyl-4-nitro- 1 H-pyrrole-2-carboxylate (3.0 g, 16.30 mmol), 80 ml of THF, 405 mg of 10% Pd/C and 1.3 ml of HCl (cone). After evacuation under vacuum the bottle was placed under 30 psi hydrogen and shaken for 5 hours. The mixture was filtered through celites, evaporated to dryness without further purification. To the dry mixture was added 1 -methyl-4-nitro- lH-pyrrole-2-carboxylic acid (2.75 g, 16.18 mmol), 80 ml of DMA, EDC (8.51 g, 44.27 mmol) and DIPEA (2.80 ml, 16.10 mmol). The mixture was stirred under Ar overnight, concentrated, diluted with THF/EtAc (1 :2, 150 ml), and washed IM NaH2PO4ZNaCl (cone) and NaHCO3 (cone) separately. The organic layer was separated and dried over MgSO4, filtered concentrated and crystal]ized with THFZH2O to afford 3.74 g (75%) of the title product. 1H NMR (DMSO) 10.25 (s, IH), 8.17 (s, IH), 7.25 (s, IH), 6.52 (s, IH), 6.08 (s, IH), 3.90 (s, 3H), 3.78 (s, 3H), 3.56 (s, 3H); 13C NMR 157.87, 156.84, 133.76, 128.16, 123.39, 119.13, 118.18, 111.83, 107.50, 104.17, 51.55, 37.41, 36.03; MS m/z+ 329.1 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester With hydrogen In ethyl acetate at 20℃; for 12h; Stage #2: di-<i>tert</i>-butyl dicarbonate In diethyl ether at 20℃; for 2h; Stage #3: With sodium hydroxide In methanol; water at 60℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester With hydrogen In ethyl acetate at 20℃; for 12h; Stage #2: 4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester With palladium 10% on activated carbon; hydrogen In ethanol; ethyl acetate at 20℃; for 11h; Stage #2: With water; lithium hydroxide at 20℃; for 1h; Stage #3: N-(9H-fluoren-2-ylmethoxycarbonyloxy)succinimide With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 12.5h; Inert atmosphere; |
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P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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