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CAS No. : | 623-04-1 | MDL No. : | MFCD00014782 |
Formula : | C7H9NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AXKGIPZJYUNAIW-UHFFFAOYSA-N |
M.W : | 123.15 | Pubchem ID : | 69331 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 36.97 |
TPSA : | 46.25 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.21 cm/s |
Log Po/w (iLOGP) : | 1.28 |
Log Po/w (XLOGP3) : | -0.22 |
Log Po/w (WLOGP) : | 0.62 |
Log Po/w (MLOGP) : | 0.88 |
Log Po/w (SILICOS-IT) : | 0.98 |
Consensus Log Po/w : | 0.71 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.89 |
Solubility : | 15.8 mg/ml ; 0.128 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.29 |
Solubility : | 62.6 mg/ml ; 0.508 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.82 |
Solubility : | 1.86 mg/ml ; 0.0151 mol/l |
Class : | Soluble |
PAINS : | 1.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
98% | at 20℃; for 0.2 h; Green chemistry | General procedure: In a round-bottomed flask (25 mL) equipped with a magnetic stirrer, a mixture of aniline (0.093 g, 1 mmol) and Co3O4 (0.006 g) was prepared. Acetic anhydride (0.102, 1 mmol) was then added to the reaction mixture and stirring was continued at room temperature for 3 min. The progress of the reaction was followed by TLC. After the reaction completion, the products was extracted with EtOAc and filtered to remove Co3O4. The organic solvent was then washed with H2O (2 x 10 mL) and saturated NaHCO3 solution and then dried over anhydrous Na2SO4. The solvent was removed under vacuum to afford the pure product. |
91% | at 20℃; for 0.1 h; | General procedure: Alcohol, phenol, and/or amine (1 mmol) were added to amixture of the ZnAl2O4SiO2 nanocomposite (100 mg) andacetic anhydride (1 mmol). The mixture was stirred at 75 °C(for alcohols and phenols) or at room temperature (for amines)for a time. The progress of the reaction was monitored by TLCand/or GC‐MS. When the reaction was completed, ethyl acetate(10 mL) was added and the mixture was filtered to separate offthe catalyst. The catalyst was washed twice with 7.5 mL ethylacetate. The combined organic phases were washed with a10percent solution of NaHCO3 and then dried over MgSO4. The solventwas removed to yield the product. If further purificationwas needed, the product was passed through a short column ofsilica gel. All products were characterized on the basis ofGC‐MS, FT‐IR, and 1H‐NMR spectral data by comparing thesespectra with those of standard samples or literature data. |
91% | at 50℃; for 0.15 h; | General procedure: In a round-bottom flask (10 mL) equipped with a magnetic stirrer, a mixture of PhNH2(1 mmol, 0.093 g) and H2O(3 mL) in oil bath (50 °C) was prepared. Magnetically recyclable nanoparticles of Fe3O4/Cu (0.05 mmol) was then added, and the mixture was stirred for 1 min under oil bath conditions. Addition of Ac2O(1 mmol, 0.102 g) to the prepared mixture was followed by stirring for 3 min at 50 °C. After completion of the reaction, the copper nanocatalyst was separated by an external magnet and the mixture was extracted with EtOAc (3 × 8 mL). Organic layers were then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure affords the pure acetanilide in 95percent yield (0.128 g, Table 2, entry 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuranHeating / reflux | To a solution of p-amino-benzylalcohol (1 g, 8.12 mmol, 1 eq) in 80 mL of anhydrous THF were added DIEA (1.4 mL, 8.12 mmol, 1 eq) and BoC2O (1.9 mL, 8.12 mmol, 1 eq). The mixture was heated to reflux overnight, then cooled down and evaporated under vacuum. The residue was dissolved in EtOAc. The organic layer was washed with a 0.1 N HCl solution, dried over MgSO4, filtered and evaporated under vacuum. The crude product was purified by <n="74"/>column chromatography on silica gel (Hex-EtOAc, 1:1, v/v) to give 1.85 g of product (quantitative yield): 1H NMR δ 0.1.49 (9H, s), 2.17 (IH, s), 4.53 (2H5 s), 6.83 (IH, s), 7.19 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.2 Hz); 13 C NMR δ 28.28, 64.54, 80.37, 118.49, 127.59, 135.31, 137.46, 152.72. |
98% | for 18 h; | To a 250 mL round bottom flask was added (4-amino-phenyl)-methanol (4.13 g, 33.6 mmol), dichloromethane (50 mL) followed by di-tert-butyl dicarbonate (8.5 g, 36.9 mmol). The mixture was allowed to stir for 18 h under a nitrogen atmosphere. By TLC, a small amount of starting amine remained, which reacted during concentration by rotary evaporation. The product was purified by column chromatography (ethyl acetate : hexanes, 1:1) to yield (4- hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (7.36 g, 33.0 mmol, 98 percent) as a white solid. |
98% | at 80℃; for 0.166667 h; Green chemistry | General procedure: The reactions were carried out in a 50 mL RB flask under reduced pressure for 10 min at 80°C unless reported differently. In a typical experiment, 5 mmol of amine was added to 5 mmol of BOC anhydride, and the reaction was allowed to proceed for 10 min. The desired product was obtained in a rotary evaporator under vacuum conditions. |
87% | With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 1.5 h; | PREPARATION 15; Preparationof teri-buty\\ 4-(chloromethyl)phenylcarbamate; A. To a stirred solution of 4-aminobenzyl alcohol ( 1.50 g. 12.18 mmol) in 1.4-dioxane (30 mL) was added sodium hydroxide (0.49 g. 12.2 mmol) in water (30 mL). The mixture was cooled to 0 0C. and di-/1H NMR (300 MHz. CDCl3) δ 7.37-7.26 (m. 4H). 6.52 (br s. I H). 4.63 (s, 2H). 1.52 (s. 9H); MS (ES+) m/z 246.3 (M + 23). |
83% | With triethylamine In tetrahydrofuran at 20 - 50℃; | A i00-mL, three-necked, round-bottomed flask, was equipped with a magnetic stimng bar, a retlux condenser, and a pressure-equalizing dropping funnel that was connected to a nitrogen flow line and charged with a solution of 97percent di-tert-butyl dicarbonate (4.04 g, 18.5 nimol) in tetralydrofuran (30 mid). Amino benzyi alcohol (2.5 g, 20.3 mmol) was placed in the flask and suspended in tetrahydrofuran (65 mL) and 99percent triethylamine (3.1 mL, 22 mmoi). The resultmg white suspension was cooled with an ice-water bath and the solution of di-tert-butyl dicarbonate was added dropwise over a period of 30 minutes. After 10 mm of additional stirring, the ice-water bath was removed and the suspension was stirred overnight at room temperature, then warmed at 50°C for a further 3 hours. T he solvent was removed tinder reduced pressure and the residue partitioned between EtOAc (50 mL) and saturated aqueous bicarbonate solution (50 mL). The aqueous phase was extracted with three 50-ni. portions of EtOAc. The combined organic phases were dried with anhydrous MgSO4 and concentrated under reduced pressure to give 3.72 g (83percent yield) of the product as a brown oil that was used without further purification. ‘H NMR (as rotamers) (400 MHz, CDCh) 6 9.26 (s, I H), 8.64 (s, iH), 7.39 (.4H), 7.20 (4H), 5,75 (s, 1H), 5.05 (2H), 4.49 —4.35 (m, 4H), i.47 (s, 9H), 1.40 (s, 1H). |
82% | With triethylamine In 1,4-dioxane at 20℃; | Intermediate 10: tert-butyl 4-(hydroxymethyl)phenylcarbamateTo a solution of p-aminobenzyl alcohol (38,2 mmol) in 100 ml dioxane were added triethylamine (114 mmol) and di-tert-butyldicarbonate (42,0 mmol) was added in portions. The mixture was stirred overnight at room temperature. The solvent was evaporated. EtOAc was added and washed with 2N HCI, saturated NaHCO3 and brine solution. The organic layer was dried over Na2SO4 and evaporated to yield a brown oil.Yield: 82 percent, MS (ESI) m/z 224.3 [M+H]1H-NMR (ODd3, 400 MHz) 51.54 (s, 9H), 4.65 (s, 2H), 6.54 (s, 1H), 7.22-7.43 (m, 4H). |
74% | With acetic acid In tetrahydrofuran; water at 20℃; for 18 h; Inert atmosphere | tert-Butyl (4-(hydroxymethyl)phenyl)carbamate 19. To a solution of ra-aminobenzyl alcohol (0.123 g, 0.0999 mmol) in AcOH (10percent in water, 8 mL) was added a solution of di-feri-butyl dicarbonate in THF (1 M, 1.05 mL, 1 .05 mmol), and the reaction was stirred for 18 h at ambient temperature. Water (30 mL) was added, and the mixture was basified with a NaOH solution (2 M) to pH 14. The resulting mixture was extracted with Et20 (3 χ 30 mL). The combined organic layer was washed with water (2 x 1 5 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to afford boc-protected aminobenzyl alcohol 19 (0.166 g, 0.743 mmol, 74percent yield) as a light yellow solid. [000219] NMR (600 MHz, CDC13) δ 7.34 (2H, d, J = 8.0 Hz), 7.28 (2H, d, J = 8.4 Hz), 4.62 (2H, s), 1 .52 (9H, s). [000220] 13C NMR (150 MHz, CDC13) δ 152.9, 138.0, 135.6, 128.0, 1 18.7, 65.1 , 31.3, 28.5. [000221] HRMS: Obsvd 246.1 102 [M + Na]+, Calcd for C12H17NNa03: 246.1 101. |
59% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; | To a solution of (4-aminophenyl)methanol (30, 8.0 g, 65.0 mmol) in THF (50 mL) were added Boc2O (21.3 g, 97.5 mmol) and DIEA (16.8 g, 130.0 mmol) at rt, and the resulting mixture was refluxed overnight. The reaction mixture was concentrated and purified by column chromatography (silica gel, eluted with 1:10 MeOH/DCM) to yield 31 (8.6 g, 59percent) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 1.53 (9H, s), 4.54 (2H, s), 7.26 (2H, d, J = 8.4 Hz), 7.38 (2H, d, J = 8.4 Hz). MS (API): m/z 206.0 (M + H - H2O)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; triethylamine In N,N-dimethyl-formamide at 20℃; | Preparation of 4-((tert-butyldimethyIsilyloxy)methyI)aniline; To a solution of (4-aminophenyl)methanol (3 g, 24.36 mmol) in DMF (85 mL) was added DMAP (0.982 g, 8.04 mmol) and triethylamine (4.07 mL, 29.2 mmol). Tertbutylchloro- dimethylsilane (4.04 g, 26.8 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered to remove the salt. The filtrate was concentrated to afford 7.9 g of a red solid, which was dissolved in EtOAc (200 mL), washed with water (100 mL), saturated ammonium chloride (2 x 50 mL), water (2 x 50 mL) and brine (50 mL), the organic layer was dried over Na2SO4. Filtration and concentration afforded 4- <n="153"/>((tertbutyldimethylsilyloxy)methyl)aniline (5.66 g, 23.84 mmol, 98percent yield) as a red oil. LCMS (Table 1, Method a) R, = 3.10 min, m/z 238.19 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.94 (d, 2H), 6.51 (d, 2H), 4.95 (s, 2H), 4.49 (s, 2H), 0.87 (s, 9H), 0.03 (s, 6H). |
96% | With 1H-imidazole In dichloromethane at 20℃; for 1 h; | To a solution of (4-Aminophenyl)methanol (1.50 g, 12.18 mmol) in CH2CI2 (20 ml.) was added TBDMSCI (1.84 g, 12.18 mmol) and imidazole (0.91 g, 13.40 mmol). After stirring for 1 h at room temperature, the solution was diluted with brine, and extracted with E-tOAc. The organic extract was dried (Na2SO4), filtered, and evaporated. The residue was purified by silica gel column chromatography with gradient of EtOAc (25-100percent) in Hexane to afford 67 (2.76 g, 96percent) as a light yellow oil. LRMS (ESI): (calc.) 237.4; (found) 238.2 (MH) + |
82% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 0.25 h; | A- Aminobenzyl alcohol (1.5 grams, 12.18 mmol, 1 equivalent) and imidazole (830 mg, 12.18 mmol, 1 equivalent) were dissolved in DMF and cooled to 0 0C. Thereafter TBDMS-CI (1.836 grams, 12.18 mmol, 1 equivalent) was added and the reaction stirred for 15 minutes at room temperature. EtOAc was then added, the organic phase washed with saturated NH4CI and dried over MgSO4. Flash chromatography afforded the protected alcohol Compound A (2.36 grams, 82 percent yield, CAS No. 131230-76-7). |
82% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 5 h; | To a solution of 4-aminobenzyl alcohol (2.0g, 16.24mmol) in dry DMF (20mL) were added tert-butyldimethylsilyl chloride (3.67g, 24.35mmol) and imidazole (2.21g, 32.46mmol), the resulting mixture was further stirred for 5hat room temperature. The reaction mixture was then diluted with saturated brine solution and extracted with CH2Cl2. The organic layer was separated and washed with brine solution for several times, then dried over anhydrous Na2SO4, evaporated under vacuum, the obtained brown residue was purified by silica gel chromatography (petroleum ether-ethyl acetate), a brown oil was obtained (3.15g, 82percent). 1H NMR (CDCl3, 400MHz) δ7.12 (d, 2H, J=8.4Hz), 6.67 (d, 2H, J=8.0Hz), 4.62 (s, 2H), 3.80 (brs, 2H), 0.91 (s, 9H), 0.08 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 48 h; Darkness | DCM/MeOH=2/1 mixed solvent 60 ml was added to the reaction flask, followed by addition of Fmoc-vc2g (4.2 mmol) and1.04 g (2 eq) of PABOH was added. After stirring the dissolved portion, 2.0 g (2 eq) of EEDQ was added. The reaction system is protected from light at room temperatureStir the reaction for 2.0 days. After completion of the reaction, the mixture was concentrated under reduced pressure at 40°C to give a white solid. Collect white solids and add methyl tert-butylEthyl ether (100 ml) was stirred and filtered, and the filter cake was washed with methyl tert-butyl ether. The resulting white solid was dried at 40 °C under reduced pressure to give 2.2 g.About 88percent |
85% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 36 h; Darkness; Inert atmosphere | Fmoc-Val-Cit-PABOH 2. To a solution of Fmoc-protected dipeptide 1 (0.30 g, 0.60 mmol) in CH2Cl2/MeOH (2: 1 , 9 mL) was added P-aminobenzyl alcohol (0.12 g, 0.98 mmol ) and EEDQ (0.24 g, 0.98 mmol), and the reaction mixture was stirred in the dark for 1.5 d. The solvents were evaporated, and the resultant was triturated with Et20 (25 mL). The resulting suspension was sonicated for 20 min and left to stand for 30 min. The crude product was collected by filtration and then purified by flash chromatography using a pre-packed 50 g silica column [solvent A: MeOH; solvent B: CH2C12; gradient: 0percentA / 100percentB (1 CV), 0percentA / 100percentB -→ 20percentA / 80percentB (10 CV), 20percentA / 80percentB (2 CV); flow rate: 40 mL/min; monitored at 254 and 280 nm] to afford Fmoc-protected compound 2 (0.31 g, 0.51 mmol, 85percent yield) as a brown solid. [000188] NMR (500 MHz, DMSO-d6) 6 10.00 (1 H, s), 8.13 (1 H, d, J = 7.7 Hz), 7.92 (2H, d, J = 7.5 Hz), 7.81 - 7.71 (2H, m), 7.57 (2H, d, J= 8.4 Hz), 7.49 - 7.40 (3H, m), 7.35 (2H, t, J= 7.4 Hz), 7.26 (2H, d, J = 8.3 Hz), 5.99 (1 H, t, J = 6.5 Hz), 5.43 (2H, s), 5.12 (1 H, t, J= 5.6 Hz), 4.45 (2H, d, J= 5.4 Hz), 4.32 (1H, d,J= 10.1 Hz), 4.29 - 4.19 (3H, m), 4.00 - 3.88 (1H, m), 3.12 - 2.91 (2H, m), 2.09 - 1.94 (1H, m), 1.80-1.31 (4H, m), 0.90 (3H, d, .7=6.6 Hz), 0.88 (3H, d,J=6.7 Hz). [000189] I3C NMR (125 MHz, DMSO-d6) δ 171.7, 170.9, 159.3, 156.6, 144.4, 144.2, 141.2, 138.0, 137.9, 128.1, 127.6, 127.4, 125.8, 120.6, 119.3, 66.2, 63.1, 60.6, 47.2,30.9,30.0, 27.3, 19.7, 18.8, 15.0. |
82% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol at 20℃; for 36 h; | Fmoc-val-cit (1 eq),Add 2 eq of p-aminobenzyl alcohol (2 eq) to DMC / MeOH (2: 1), add EEDQ (2 eq) and shake for 1.5 days at room temperature.After completion of the reaction, the solvent is dried and precipitated with ether. Repeat after filtering with Ether. Yield: yellow solid 82percent. |
77% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 40℃; | Step 3 Synthesis of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (92) To the suspension of compound 90 (70 g, 0.141 mol) in DCM/MeOH (1 L/500 mL) was added compound 91 (34.7 g, 0.282 mol) followed by EEDQ (69.7 g, 0.282 mol). The mixture was stirred at 40° C. overnight. The reaction mixture was filtered and the wet cake was suspended in EtOAc/TBME (500 mL/200 mL) and stirred for 30 min, then filtered. The solid was washed with EtOAc/TBME to provide compound 92 as off-white solid 65 g (77percent). 1H NMR (400 MHz, DMSO-d6) δ=9.98 (s, 1H), 8.11 (d, 1H), 7.87 (d, 2H), 7.77 (m, 2H), 7.52 (d, 2H), 7.39 (m, 3H), 7.30 (m, 2H), 7.21 (d, 2H), 5.97 (m, 1H), 5.41 (s, 2H), 5.10 (m, 1H), 4.42 (m, 3H), 4.22 (m, 3H), 3.90 (m, 1H), 2.93 (m, 2H), 1.98 (m, 1H), 1.50 (m, 2H), 1.30 (m, 2H), 0.84 (m, 6H). |
76% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; | A solution of compound 28 (1 g, 2.01 mmol, leq) andp-aminobenzyl alcohol (273 mg, 2.21 mmol, 1.1 eq) in a mixture of DCM/MeOH (20 mL/10 mL) was treated with EEDQ (996 mg, 4.03 mmol, 2 eq). The mixture was stirred in the dark at room temperature overnight. The solvents were removed under vacuum and the resulting solid residue was triturated with 10 mL of ethyl ether. The solid was collected by filtration and washed with ethyl ether to yield the product (925 mg, 76percent yield): 1H NMR (DMSO- |
65% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16 h; Darkness | EEDQ (840 mg, 3.4 mmol) is added to a solution containing compound [12] (870 mg, 1 .7 mmol) and p-aminobenzyl alcohol (227 mg, 1 .8 mmol) in dichloro- methane/methanol 2:1 (15 mL). The reaction is left in the dark at room temperature for 16 hours. The solvents are removed, and the resulting solid residue filtrated using diethyl ether to give product [14] as a white solid, 660 mg (65percent yield). MS: m/z 624 [M+Na]+.1H NMR (400 MHz, DMSO) δ 10.00 (bs, 1 H), 8.13 (m, 4H), 7.92 (d, J = 7.3 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.51 - 7.10 (m, 2H), 6.02 (s, 1 H), 5.43 (m, 4H), 5.13 (s, 1 H), 4.47 (s, 3H), 4.31 (m 4H), 3.13 - 2.74 (m, 2H), 2.03 (s, 1 H), 1 .83 - 1 .55 (m, 2H), 1 .43 (s, 2H), 0.90 (d, J = 6.7 Hz, 6H).13C NMR (101 MHz, DMSO) δ 171 .2, 170.4, 158.93, 156.15, 144.6, 143.8, 140.7, 137.5, 127.6, 127.2 (2C) 125.3, 120.1 (2C), 1 18.9, 65.7, 62.6, 60.1 , 53.0, 46.7, 31 .0, 30.5, 26.7, 19.6, 18.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With copper(I) chloride; potassium borohydrate In methanol for 0.416667h; Ambient temperature; | |
100% | With hydrazine hydrate monohydrate In ethanol at 78℃; for 24h; | |
100% | With hydrogen In methanol at 20℃; for 5h; |
100% | With C37H23Cl2N7Pd2(2+)*2F6P(1-); hydrogen; sodium cyanotrihydridoborate In methanol at 50℃; for 6h; | |
99% | With hydrogen at 20℃; for 1h; | |
99% | With borane-ammonia; Pd/MIL-101 In methanol; lithium hydroxide monohydrate at 20℃; for 0.025h; | |
99% | With hydrazine hydrate monohydrate In ethanol at 40℃; for 0.5h; | |
99% | With hydrogen In ethanol; lithium hydroxide monohydrate at 25℃; for 4h; Schlenk technique; | 4 Example 4 Evaluation of catalytic activity of polyamic acid salt supported platinum nano-catalyst in water and ethanol mixed solvent 0.2 mmol of nitro compound,2 mL of the polyamide salt supported platinum nanocatalyst solution and 1 mL of ethanol were addedSchlenk tube.Schlenk tube connected to the H2 balloon,And then use the pump to vacuum, repeated replacement H2 more than three times. Reaction solution After vigorous stirring at room temperature and atmospheric pressure H2. To monitor the progress of the reaction, each time to sample ~ 30μL, with ethyl acetate multiple extraction, the organic phase, combined with gas chromatography analysis, the results shown in Table 2. |
99% | With C20H32Cl4Cu2N4O4 In lithium hydroxide monohydrate at 60℃; for 1h; Inert atmosphere; Schlenk technique; | 2.4. General procedure for the reduction of nitro compounds withcopper complex catalyst General procedure: Copper complex (0.001 mmol, 1mol%), appropriate nitro compounds (0.1 mmol, 1.0 equiv) and NaBH4 (10.0 mmol, 10 equiv)in water (2.0 mL) were charged into a 15 mL pressure tube under air atmosphere. Subsequently, the resulting mixture was stirred atroom temperature in closed vessel. After completion of the reaction(monitored by TLC), the crude reaction mixturewas extraction with ether (3 2 mL), and analyzed by GC-MS chromatography using n-dodecaneas an internal standard. |
99% | With borane-ammonia; N-hexadecyl-N,N,N-trimethylammonium bromide; [Ru(p-cymene)(2,6-bis(1-methylimidazole-2-thione)pyridine)](PF6)2 In lithium hydroxide monohydrate; acetonitrile at 79.84℃; for 3h; Inert atmosphere; Schlenk technique; | |
98% | With isopropanol; sodium hydroxide for 5h; Inert atmosphere; Reflux; chemoselective reaction; | |
98% | With sodium tetrahydridoborate; PdCu/graphene (2 mol % Pd) In ethanol; lithium hydroxide monohydrate at 0 - 50℃; | 4.3 General procedure for reduction of aromatic nitro compound using PdCu/graphene16 General procedure: A mixture of nitroarene (1 mmol), PdCu/graphene (6 mg) and sodium borohydride (2mmol) were taken in a 25 mL reaction tube. 3 mL of EtOH:H2O (1:2 in volume ratio) was added by a syringe at 0°C. After 10 min the reaction mixture was placed in an oil bath at 50°C. The reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried over anhydrous Mg2SO4. Evaporation of the combined organic layer and followed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines. |
98% | Stage #1: (4-nitrophenyl)methanol With copper ferrite In lithium hydroxide monohydrate for 0.5h; Reflux; Green chemistry; Stage #2: With sodium tetrahydridoborate In lithium hydroxide monohydrate for 1.16667h; Reflux; Green chemistry; | General procedure for the reduction of nitro compounds to amines General procedure: For example, in a round-bottom flask (15 mL) equipped with a magnetic stirrer, a mixture of nitrobenzene (1 mmol, 0.123 g) in H2O (2 mL) was prepared. CuFe2O4 (0.2 mmol, 0.048 g) was then added, and the mixture was stirred. At the next step, NaBH4 (2 mmol, 0.076 g.) was added, and the resulting mixture continued to stir at reflux for 50 min. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, and the mentioned nanocatalyst was separated by an external magnet. The reaction mixture was extracted with EtOAc (2 x 4 mL) and then dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to afford the pure liquid aniline in 95% yield. |
98% | Stage #1: (4-nitrophenyl)methanol In lithium hydroxide monohydrate at 20℃; for 0.0833333h; Stage #2: With sodium tetrahydridoborate In lithium hydroxide monohydrate at 75℃; for 0.166667h; | 2.3.4 Synthesis of amines catalyzed using CoO(at)N-mC General procedure: To a 10mL round-bottom flask equipped with a magnetic stirrer, CoO(at)N-mC nanocatalyst (30mg), nitroarene (1.0mmol), and H2O (3mL) were added and the reaction mixture was stirred at ambient temperature for 5min, then NaBH4 (3mmol) was added and the resulting mixture heated in an oil bath at 75°C for an appropriate time. After the finishing of the reduction reaction that was followed by applying TLC, CoO(at)N-mC nanocatalyst was separated with the centrifuge, rinsed with ethanol, dried at 60°C to be ready for the next cycle without any purification. After isolation of catalyst, the product was extracted with ethyl acetate and purified by short column chromatography on silica gel, if necessary, to obtain the relevant compound in desired purity. |
98% | With methanol; sodium tetrahydridoborate at 20℃; for 1h; Green chemistry; | 2.3. Catalytic hydrogenation of nitroarenes for PdCS General procedure: In a typical procedure: 0.25 mmol nitrobenzene, 2 mL solvent(MeOH, CH2Cl2, xylene, etc), 0.6 mmol NaBH4, and 0.2 mol% [Pd] (Pd:substrate, mol%) were placed in a flask equipped with a magnetic stirrer.The reaction mixture was stirred for several hours at room temperatureand detected by gas chromatography (GC). For the substratesuitability test of nitro compounds, 0.25 mmol aromatic nitro compounds,2 mL MeOH, 0.6 mmol NaBH4, and 0.2 mol% [Pd] (Pd: substrate,mol%) were placed in a flask equipped with a magnetic stirrer.The reactions were stirred for several hours at room temperature, andthe yields were isolated yields, with 1H NMR spectra in the supportinginformation. |
97% | With sodium tetrahydridoborate; lithium hydroxide monohydrate at 20℃; for 0.5h; Green chemistry; | |
96% | With gold nanoparticles supported on titanium dioxide (TiO<SUB>2</SUB>); ammsnium formate In ethanol at 25℃; for 3h; Inert atmosphere; chemoselective reaction; | |
96% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 20℃; for 0.05h; | |
96% | With sodium tetrahydridoborate; cyclohexanediamine-Pd-β-cyclodextrin In lithium hydroxide monohydrate at 20℃; for 3h; Sealed tube; | |
96% | With sodium tetrahydridoborate; C23H23Cl2NORu In ethanol at 30℃; for 20h; | |
96% | With C20H24ClNO2Ru; isopropanol; potassium hydroxide at 89.84℃; for 3h; Sealed tube; Green chemistry; | |
96% | With sodium tetrahydridoborate In ethanol; lithium hydroxide monohydrate at 45℃; for 2h; Green chemistry; | |
96% | With C12H12ClN2ORu(1+); hydrazine hydrate monohydrate In ethanol; lithium hydroxide monohydrate at 80℃; for 24h; | |
95% | With sodium tetrahydridoborate; pyrographite In tetrahydrofuran; lithium hydroxide monohydrate at 50 - 60℃; for 2h; | |
95% | With sodium tetrahydridoborate; antimony(III) fluoride In lithium hydroxide monohydrate; acetonitrile at 20℃; for 0.0833333h; | |
95% | With NiRh3; hydrogen In ethyl acetate at 20℃; for 12h; chemoselective reaction; | |
95% | With trichlorosilane; N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 20℃; for 18h; Inert atmosphere; | |
95% | Stage #1: (4-nitrophenyl)methanol With CoCl2(thiourea)2 at 20℃; for 0.0166667h; Cooling with ice; Stage #2: With sodium tetrahydridoborate at 20℃; for 0.25h; Cooling with ice; | |
95% | With palladium 10% on activated carbon; hydrazine hydrate monohydrate In methanol at 20℃; for 16h; | 5 P-nitrobenzyl alcohol (15.30 g, 100.0 mmol) and 0.31 g palladium on carbon (10% Pd/C) plusInto anhydrous methanol (150 mL), slowly add 20 mL of hydrazine hydrate (N2H4·H2O).After stirring at room temperature for 16 hours, the methanol was removed by rotary evaporation, extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate.Remove the ethyl acetate by rotovap.The resulting p-aminobenzyl alcohol (11.70 g, yield 95.0%) was directly subjected to the next reaction. |
95% | With sodium tetrahydridoborate In ethanol; lithium hydroxide monohydrate at 20℃; for 0.5h; | |
95% | With sodium tetrahydridoborate In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 5h; Green chemistry; | |
95% | With sodium tetrahydridoborate; lithium hydroxide monohydrate for 0.416667h; Heating; | 3.4. General Procedure for the Reduction of Nitroarenes Catalyzed by GO-Chit-Ni NPs General procedure: In a round bottom flask, 3 mg of the catalyst GO-Chit-Niwas dispersed in 5 mL of water by sonication for 20 min atambient temperature. Then, NaBH4 (4 mmol) was poured into the flask containing catalyst. Next, the reaction mixture was placed into oil bath with a agitating at 60°C, and the nitroarene (1 mmol) was poured into the solution. At the end of the reaction (as controlled using TLC), reaction mixture was filtered. Next, the mixture was cooled to ambient temperature and separated using diethyl ether (3 × 10 mL). The aryl amine was isolated using column chromatography on silica-gel with suitable eluent of n-hexane and ethyl acetate. All of the products were known compounds, and their NMR spectra were in accordance with those reported in the literature[39]. Aniline (Table 3, entry 1): 1H NMR (300 MHz, CDCl3):δ 7.27 -7.08 (m, 2H), 6.87-6.61 (m, 3H), 3.56 (s, 2H); 13CNMR (75 MHz, CDCl3): δ 148.1, 129.7, 119.8, 114.7. |
95% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 75℃; for 2h; Green chemistry; | 2.4. The catalytic activity of PSeCN/Ag in the reduction of nitroarenes General procedure: Typically, 4-nitroaniline (1 mmol), NaBH4 as reducer (5 mmol), PSeCN/Ag nanocatalyst (20 mg) were added into a 10 mL vial containing 3 mL H2O as the solvent. Then, the reaction mixture was stirred for a certain time at 75 °C. The reaction was checked by TLC. Upon the completion of the reaction, the PSeCN/Ag was isolated by centrifugation and washed with EtOH and H2O to use for another consecutive run. Then, the product was extracted with ethyl acetate and purified by plate or column chromatography. |
94% | With hydrogenchloride; indium powder In tetrahydrofuran at 20℃; for 1h; | |
94% | With trimethylamine-borane In methanol for 2h; Heating; | |
94% | With sodium tetrahydridoborate; NiCl2·6H2O In lithium hydroxide monohydrate; acetonitrile at 20℃; for 0.0833333h; | |
94% | With sodium tetrahydridoborate In ethanol; lithium hydroxide monohydrate at 60℃; for 1.5h; | |
94% | With sodium tetrahydridoborate; lithium hydroxide monohydrate In neat (no solvent) at 20℃; for 0.05h; Milling; | General procedure: As a representative example, a mixture of nitrobenzene(1 mmol), Ni2BCu2O (54 mg), 1 drop of distilled water, and NaBH4 (2.5mmol) was ground using a simple porcelainmortar and pestle for 1 min at room temperature. After completion of the reaction (checked by TLC), distilled water(5mL) was added to the reaction vessel, and subsequently the reaction mixture transferred to a round-bottom flask (25mL) equipped with a magnetic stirrer. The mixture was stirredvigorously for 2min. Next, the product was extracted with dichloromethane (53mL). The extracts were dried with anhydrous sodium sulfate and then passed through a cottonfilter. Evaporation of the solvent afforded pure aniline in 98%yield. |
94% | With sodium tetrahydridoborate In ethanol; lithium hydroxide monohydrate at 20℃; for 4h; Green chemistry; | 4.5 General procedure for the reduction of nitro aromatic using starch-crt(at)Au General procedure: To a flask containing nitroarene (0.5 mmol), starch-crt(at)Au (0.1 mol%, 25 mg) and NaBH4 (2.5 mmol, 45 mg), 2 mL of H2O:EtOH (1:1) was added. Reaction mixture was stirred at room temperature for the appropriate reaction times (see Tables 2 and 3). Progress of the reactions were monitored by GC, TLC and or 1H NMR. After completion of the reaction, the crude product was extracted with ethyl acetate (3 × 5 mL). The solvent was evaporated and the residue was purified using column or plate chromatography. |
94% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 60℃; for 0.05h; | 2.6. A typical procedure for reduction of nitrobenzene to aniline withNaBH4/MMTFe3O4Cu MNPs system General procedure: In a round-bottom flask (10 mL) containing H2O (2 mL),nitrobenzene (0.123 g, 1 mmol) and MMTFe3O4Cu MNPs(20 mg) was added and the resulting mixture was stirred vigorouslyin an oil bath (60 °C) for 3 min. Next, NaBH4 (0.114 g,3 mmol) was added to the prepared suspension and the mixturewas stirred under oil bath conditions (60 °C) for additional 5 min.Completion of the reaction was monitored by TLC (eluent: n-hexane:EtOAc = 5:1). After that, the magnetic nanocatalyst was separatedfrom the reaction mixture using an external magnetic field.The mixture was then extracted with EtOAc (2 x 4 mL) and thecombined extracts were dried over anhydrous Na2SO4. Evaporationof the solvent under reduced pressure affords the pure liquid anilinein 96% yield (0.0894 g, Table 4, entry 1). |
94% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 55℃; for 0.416667h; Green chemistry; | Typical method for the reduction of nitroarenescatalyzed by Pd-porphyrin(at)polymer General procedure: In a round bottom flask, nitrobenzene (1 mmol), NaBH4(4 mmol), catalyst (15 mg), and water were added and heated at 55 °C, then, reacted for the required time. Thecompletion of the reaction was monitored by TLC, usingethyl acetate/ n-hexane (1:10) as eluent. After the finalizationof the reaction, the Pd-porphyrinpolymer wasseparated from the reaction mixture by filtration. Then,the product was extracted from the liquid with Et2Oandpurified by column chromatography using n-hexane/ ethylacetate as solvent to obtain the pure compound. |
94% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 20℃; for 6h; Schlenk technique; | 2.5. Procedure of catalysis experiments General procedure: To investigate scope of the substrate, a nitroarene (0.250 mmol),sodium borohydride (1.50-2.00 mmol), de-ionized water (2.00 mL)and Pd-[P(NA)] (2.50 mL) were stirred in a Schlenk tube at room temperature. Reaction progress was examined by TLC. Ethyl acetate(EtOAC) was used for extraction of crude mixture. The final product was obtained by loading the crude mixture on silica gel column. Tetramethylsilane (TMS) was as internal standard for NMR measurements on Bruker 400 MHz NMR spectrometer. |
93% | Stage #1: (4-nitrophenyl)methanol In lithium hydroxide monohydrate; acetonitrile at 20℃; for 0.0833333h; Stage #2: With sodium tetrahydridoborate In lithium hydroxide monohydrate; acetonitrile at 20℃; for 0.583333h; | |
93% | With hydrogen In ethanol at 20℃; for 1h; | |
93% | With sodium tetrahydridoborate In ethanol; lithium hydroxide monohydrate at 45℃; for 0.166667h; | |
93% | With sodium tetrahydridoborate; C27H23ClF3NORu In ethanol at 20℃; for 1.5h; Schlenk technique; Inert atmosphere; | 2.3. General procedure for the reduction of nitroarenes to anilines withthe half-sandwich ruthenium catalysts General procedure: The half-sandwich ruthenium complex (0.0015 mmol, 0.05equiv.) was dissolved in ethanol (2.0 mL), then the appropriatenitroarene (0.3 mmol, 1.0 equiv.) and NaBH4 (1.2 mmol, 4.0 equiv.) was added. Subsequently, the resulting mixture was stirred atroom temperature in a closed vial. After completion of the reaction(monitored by TLC), the mixture was quenched with water (2 mL)and extracted with EtOAc (3 2 mL). After the solvents wereremoved in vacuo from the combined organic extracts, the crudeproducts were loaded directly onto a column of silica gel and purifiedby column chromatography to yield the corresponding products. |
93% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 20℃; for 0.116667h; Green chemistry; | |
92% | With sodium tetrahydridoborate; lithium hydroxide monohydrate; nickel at 20℃; for 2h; | |
92% | Stage #1: (4-nitrophenyl)methanol With nickel boride In lithium hydroxide monohydrate at 20℃; for 0.0833333h; Green chemistry; Stage #2: With sodium tetrahydridoborate In lithium hydroxide monohydrate at 20℃; for 0.5h; Green chemistry; | A typical procedure for reduction of nitrobenzene to anilinewith NaBH4/additive Ni2B system General procedure: In a round-bottomed flask (10 mL) equipped with a magneticstirrer, a mixture of nitrobenzene (0.123 g, 1 mmol)and H2O (2 mL) was prepared. Ni2B (0.006 g, 0.05 mmol) was then added and the mixture was stirred for 5 min.NaBH4 (0.095 g, 2.5 mmol) was also added and the resultingmixture was continued to stirring for 3 min at roomtemperature. TLC monitored the progress of the reaction(eluent, n-hexane/Et2O:5/3). After completion of the reaction,aqueous solution of KOH (2 %, 5 mL) was addedand the mixture was stirred for 10 min. The mixture wasextracted with EtOAc (3 × 8 mL) and then dried overanhydrous Na2SO4. Evaporation of the solvent affords thepure liquid aniline in 95 % yield (0.088 g, Table 2, entry 1). |
92% | With sodium tetrahydridoborate; C22H22Cl2N2ORu In lithium hydroxide monohydrate at 20℃; for 24h; Inert atmosphere; Schlenk technique; | |
92% | With hydrazine hydrate monohydrate In methanol at 20℃; for 2h; | |
92% | With sodium tetrahydridoborate In ethanol at 24.84℃; for 3h; | |
92% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 60 - 70℃; for 0.333333h; Green chemistry; | A typical procedure for reduction of nitrobenzene General procedure: In a round-bottom flask (10 mL) containing 2 mL water, a mixture of nitrobenzene (0.123 g, 1 mmol) and Fe3O4SiO2Cu-Ni-Fe-Cr LDH (10 mg) was prepared and the resulting mixture was stirred for 5 min. Next, NaBH4(0.076 g, 2 mmol) was added and the reaction mixture was stirred magnetically for 3 min under oil bath conditions (60-70 °C). TLC monitored the progress of the reaction (eluent, n-hexane/EtOAc: 5/2). After completion of the reduction reaction, the mixture was cooled to the room temperature. EtOAc (3 mL) was then added and the resulting mixture was again stirred for 10 min. The magnetic nanocatalyst was separated by an external magnet followed by extraction with EtOAc (2 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4. Evaporation of the solvent afforded the pure liquid aniline in 95% yield (Table 2, entry 1). |
92% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 50℃; for 0.666667h; | |
92% | With sodium tetrahydridoborate; C27H25Cl2NO2Ru; N-hexadecyl-N,N,N-trimethylammonium bromide In lithium hydroxide monohydrate at 20℃; for 7h; Inert atmosphere; Schlenk technique; | |
91% | With 1,1,3,3-Tetramethyldisiloxane In ethanol at 20℃; for 24h; Inert atmosphere; Sonication; chemoselective reaction; | |
91% | With sodium tetrahydridoborate; copper In lithium hydroxide monohydrate at 80℃; for 0.0666667h; Green chemistry; | A typical procedure for reduction of nitrobenzeneto aniline with NaBH4/Cu NPs system General procedure: In a round-bottom flask (10 mL) equipped with a magneticstirrer, a mixture of nitrobenzene (0.123 g, 1 mmol)and H2O (2 mL) was prepared. Cu NPs (0.0095 g,15 mmol %) was then added, and the mixture was stirredfor 3 min at 80 °C. Afterward, NaBH4 (0.076 g, 2 mmol)was added portion wisely (two portions) with the intervalof 2 min, and the resulting mixture was continued to stirringat 80 °C. TLC monitored the progress of the reaction(n-hexane/EtOAc: 5/2). After completion of the reaction,Cu NPs was separated by filtration, and the mixture wasextracted with EtOAc (2 × 5 mL). The organic layer wasthen dried over anhydrous Na2SO4. Evaporation of the solventaffords the pure liquid aniline in 91 % yield (0.085 g,Table 2, entry 1). |
91% | Stage #1: (4-nitrophenyl)methanol With Cu(OH)x impregnated on Fe<SUB>3</SUB>O<SUB>4</SUB> In lithium hydroxide monohydrate for 0.0833333h; Green chemistry; Stage #2: With sodium tetrahydridoborate In lithium hydroxide monohydrate at 55 - 60℃; for 0.0666667h; Green chemistry; | A typical procedure for reduction of nitrobenzene to aniline with NaBH4/Nano Fe3O4-Cu(OH)x system General procedure: In a round-bottom flask (10 mL) equipped with a magnetic stirrer, a mixture of nitrobenzene (0.123 g, 1 mmol) and H2O (3 mL) was prepared. Nano Fe3O4-Cu(OH)x(20 mg, 0.06 mmol, x = 2) was then added, and the resulting mixture was stirred for 5 min. Next, NaBH4 (0.076 g,2 mmol) was added and the reaction mixture was continued to stirring for 3 min at 55-60 °C. TLC monitored the progress of the reaction (eluent, n-hexane/EtOAc: 5/2). After completion of the reaction, the nanocatalyst was separated by an external magnet and the reaction mixture was extracted with EtOAc (2 × 5 mL). Drying organic layer over anhydrous Na2SO4 and then evaporation of the solvent affords the pure liquid aniline in 95 % yield (0.088 g, Table 2, entry 1). |
90% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 45℃; for 0.133333h; | |
90% | Stage #1: (4-nitrophenyl)methanol With ferric(III) chloride; pyrographite In ethanol for 2h; Reflux; Stage #2: With hydrazine monohydrate In ethanol for 3h; Reflux; | 2.1.1 Synthesis of compound 4 4-Nitrobenzyl alcohol (3.80g, 24.8mmol) was dissolved in EtOH (30.0mL), followed by addition of FeCl3 (0.1g) and activated carbon (0.5g). After refluxed for 2h, hydrazine hydrate (5.0g, 100mmol) was added dropwise to the above mixture at the same temperature. After being stirred for another 3h, the mixture was filtered and the filter liquor was concentrated under vacuum. The obtained precipitation was purified by silica column chromatography using petroleum/ethyl acetate (2:1, v/v) to give a white solid (2.75g, 90%). 1H NMR (400 MHz, DMSO): δ=6.95 (d, J=8Hz, 2H), 6.50 (d, J=8Hz, 2H), 4.92 (s, 2H), 4.79 (t, J=8Hz, 1H), 4.28 (d, J=8Hz, 2H) (Fig.S1). 13C NMR (100 MHz, DMSO): δ=145.97, 131.13, 128.78, 115.20, 65.16 (Fig.S2). |
90% | With sodium tetrahydridoborate; chloro(p-cymene)(1-((4-nitrophenylimino)methyl)naphthalen-2-ol-κ-O,N)ruthenium(II) In ethanol at 20℃; for 2h; Inert atmosphere; Schlenk technique; | 2.2.3. General procedure for the reduction of nitroarenes to anilines with halfsandwichruthenium catalysts General procedure: The half-sandwich ruthenium complex (0.003 mmol, 0.01 equiv) was dissolved in solvent(2.0 mL), and then the appropriate nitroarene (0.3 mmol, 1.0 equiv), and NaBH4 (45.4 mg,1.2 mmol, 4.0 equiv) were added. The resulting mixture was stirred at room temperature ina closed vessel. After completion of the reation (monitored by TLC), the crude reaction mixturewas extracted with ether (3 × 2 mL). After the solvents were removed in vacuo from thecombined organic extracts, the crude products were loaded directly onto a column of silicagel and purified by column chromatography using petroleum ether and ethyl acetate (1 : 3)to get the corresponding products [27]. |
90% | With sodium tetrahydridoborate; lithium hydroxide monohydrate at 20℃; for 0.0025h; Green chemistry; | |
90% | Stage #1: (4-nitrophenyl)methanol With 7% w/w Pd/C In lithium hydroxide monohydrate Green chemistry; Stage #2: With sodium tetrahydridoborate; lithium hydroxide monohydrate for 0.116667h; Reflux; Green chemistry; chemoselective reaction; | General procedure for the reduction of nitroarenes to arylamines catalyzedby Pd/C General procedure: For example, in a round-bottom flask (15 mL) equipped with a magnetic stirrer, a mixture of PhNO2 (1 mmol, 0.123 g) and H2O (2 mL) was prepared. Then, (7wt%) Pd/C (30 mg) was added, and the mixture was stirred. At the next step, NaBH4 (2 mmol, 0.076 g) was added, and the resulting mixture continued to stir at reflux for 7 min. After completion of the reaction (monitored by thin-layer chromatography (TLC) using CCl4:ether (5:2) as an eluent), the mixture was cooled to room temperature, and the mentioned catalytic system was separated by filtration. The reaction mixture was extracted with dichloromethane (DCM)(3 × 5 mL) and then dried over anhydrous sodium sulfate (Na2SO4). Finally, the solvent was evaporated under reduced pressure to afford the pure liquid aniline in 93% yield. |
89% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 20℃; for 0.216667h; chemoselective reaction; | |
89% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 20℃; for 1.5h; chemoselective reaction; | 2.2 General procedure for aromatic nitrocompounds reduction General procedure: In a typical procedure, a mixture of 5 mL of water,an aromatic nitro compound (1 mmol) and CuNPs(5 mg) was taken in a 50 mL round-bottomed flaskand then stirred at room temperature followed by theaddition of NaBH4 (200 mg) with constant stirring.Progress of the reaction was monitor by TLC, aftercompletion of the reaction the product was extractedby ethyl acetate and purified by column chromatography on silica gel to afford the amine. A variety ofamines were prepared in this manner and characterizedby analyzing their 1H and 13C NMR spectraldata. The reported compounds were confirmed bycomparing the spectral data with literature values whereas new compounds were additionally characterizedby analyzing HR-MS data. |
89% | With sodium tetrahydridoborate In lithium hydroxide monohydrate at 20℃; for 1.5h; chemoselective reaction; | 2.2 General procedure for aromatic nitrocompounds reduction General procedure: In a typical procedure, a mixture of 5 mL of water,an aromatic nitro compound (1 mmol) and CuNPs(5 mg) was taken in a 50 mL round-bottomed flaskand then stirred at room temperature followed by theaddition of NaBH4 (200 mg) with constant stirring.Progress of the reaction was monitor by TLC, aftercompletion of the reaction the product was extractedby ethyl acetate and purified by column chromatography on silica gel to afford the amine. A variety ofamines were prepared in this manner and characterizedby analyzing their 1H and 13C NMR spectraldata. The reported compounds were confirmed bycomparing the spectral data with literature values whereas new compounds were additionally characterizedby analyzing HR-MS data. |
88% | With sodium tetrahydridoborate; lithium hydroxide monohydrate at 20℃; for 2.5h; | 2.3. Heterogeneous reduction of nitroarenes catalyzed by the CoFe2O4Pd/AC nanocomposite Reduction of nitroarenes was carried out in a 10 mL round-bottomflask equipped with a magnetic stirrer. First, 6 mg of the CoFe2O4Pd/AC was dispersed in 3 mL deionized water. Then, 1 mmol of the nitroarenewas added to the flask. With a continuous stirring at room temperature,1.5 mmol of NaBH4 in 4 mL deionized water was slowly addedto the reaction vessel during stirring. After appropriate time, thecompletion of the reaction was monitored by thin-layer chromatography(TLC). The catalyst was separated by using an external magnet from thereaction mixture. The mixture was decanted and extracted by ethyl acetateand dried over anhydrous Mg2SO4. The isolated product was obtainedby evaporating the ethyl acetate and subjected to characterizationby IR spectroscopy. |
88% | With hydrazine monohydrate In lithium hydroxide monohydrate at 20℃; for 0.75h; | 4-Aminobenzyl alcohol General procedure: To a stirred suspension of appropriate p-nitrotoluene (0.274 g, 2.0 mmol) in 3 mL water, Ni-alumina (0.125 g, 6 mol % of nickel metal) was added followed by 0.3 mL 80% hydrazine hydrate. The reaction mixture was stirred for the required period of time at room temperature till the reaction was complete (monitored with TLC). Then ethyl acetate (20 mL) was added to the reaction mixture to dissolve the product and the catalyst was separated simply by filtration. The residue (recovered catalyst) was thoroughly washed with EtOAc (4 5 mL) followed by water (2 10 mL). The aqueous reaction mixture was repeatedly extracted with ethyl acetate (3 5 mL). The combined organic extracts were washed with water (3 10 mL) and dried over anhydrous Na2SO4. The crude product was obtained by removal of the solvent under reduced pressure which was further purified by filtration chromatography on a short column. |
85% | With Ba(BH2S3)2 In tetrahydrofuran for 1.75h; Heating; | |
85% | With palladium 10% on activated carbon In methanol; ethanol at 20℃; for 24h; | 1 4.4 General procedure for the synthesis of 4-substituted anilines (5 and 6e,n) The method adopted for the synthesis of 4-aminophenylmethanol (5) is described. Catalytic hydrogenation of 4 (1.50 g, 9.8 mmol) in 30mL of a mixture of MeOH and absolute EtOH (2/1) was conducted at room temperature for 24 h in the presence of 10% palladium on carbon at 10 bar. The catalyst was removed by filtration and the residue taken up with EtOAc and washed with water. The solvent was removed to give 1.03 g (85%) of a yellow solid which was recrystallized from EtOAc/petroleum ether to give 0.65 g of yellowish crystals: mp 65-66°C; GC/MS (70eV) m/z (%) 123 (M+, 100). Other spectroscopic data were in agreement with the literature [36]. |
80% | With stannous chloride; 1-n-butyl-3-methylimidazolium trifluoromethanesulfonate at 20℃; for 0.25h; sonification; | |
79% | With C9Fe3O9Se2; hydrazine hydrate monohydrate In lithium hydroxide monohydrate at 110℃; for 0.25h; Green chemistry; | |
77% | With hydrogen In ethanol for 2h; Ambient temperature; | |
77.5% | With sodium hydrogen sulphide; lithium hydroxide monohydrate at 95℃; for 3h; | |
75% | With sodium tetrahydridoborate In methanol; lithium hydroxide monohydrate at 0 - 50℃; for 0.66h; chemoselective reaction; | Reduction in presence of NaBH4 (Method A) General procedure: A mixture of nitroarene (1 mmol), SS-Pd (2 mol% Pd) and sodium borohydride (3 mmol) were taken in a 25 ml round bottomed flask. 3 ml of MeOH:H2O (3:7) was added to the mixture by a syringe at 0 oC in stirring condition. After 10 minutes the reaction mixture was heated to 50 oC. Progress of the reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried over anhydrous Na2SO4. Evaporation of the combined organic layer and followed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines. |
55% | With Triethoxysilane; C22H27ClFeNO3 In acetonitrile at 80℃; for 6h; | |
40% | With copper(II) bis(2,4-pentanedionate); sodium tetrahydridoborate In ethanol at 20℃; for 2h; Inert atmosphere; | 5.1. 4-aminobenzyl alcohol A mixture of Cu(acac)2 (0.35 g, 1.31 mmol) and NaBH4 (0.25 g,6.53 mmol) in EtOH (70 mL) was stirred (1 h) under N2. A solutionof 4-nitrobenzyl alcohol (1.00 g, 6.53 mmol) in EtOH (70 mL) was added followed by NaBH4 (0.50 g, 12.06 mmol). The mixture was stirred (2 h), distilled water (120 mL) was added and the mixture was filtered. The filtrate volume was reduced by evaporation of most of the EtOH and the remaining solution was extracted with CH2Cl2 (2 50 mL). The combined organic extracts were dried (MgSO4) and evaporated to yield a brown viscous oil which solidified upon standing yielding compound 13 (0.32 g, 40%). This product was used directly without further purification. 1H NMR(400 MHz d6-DMSO) d 6.91 (2H, d, J = 8.2 Hz, Ar-H), 6.46 (2H, d,J = 8.2 Hz, Ar-H), 4.88 (2H, br s, NH), 4.75 (1H, t, J = 5.4 Hz, OH),4.24 (2H, d, J = 5.4 Hz, CH2). |
23% | With lithium hydroxide monohydrate; calcium(II) chloride; zinc for 0.5h; Reflux; | Experimental 4-Nitrobenzyl alcohol (20 g, 0.12 mol) was added to a boiling suspension of zinc dust (80 g, 1.22 mol) and calcium chloride (8 g, 0.07 mol) in water (400 mL). The resulting solution was boiled for 30 min and then filtered hot. On cooling the filtrate, a reddish solid appeared and this wasfiltered off and discarded. Sodium carbonate was then addedto the filtrate to precipitate the calcium salts, which werethen filtered off. The filtrate was evaporated down to dryness.The resulting oil was then recrystallized from tolueneto afford a pale yellow solid (3.69 g, 23%) m.p. 60-61 °C,(lit. [7] 58-61 °C).δH (Bruker AV400, 400 MHz, CDCl3)7.18 (2H, d,J = 8.5 Hz, ArH) 6.69 (2H, d, J = 8.5 Hz, ArH), 4.57 (2H, s,CH2OH)and 3.65 (2H, s, NH2)(agreement with lit. values[8]). |
5% | Stage #1: (4-nitrophenyl)methanol With trichloromethane sulfonic Acid; Wang resin trichloroacetimidate In dichloromethane for 0.166667h; Stage #2: With indium powder; ammonia hydrochloride for 5h; Heating; Stage #3: With trifluoroacetic acid In dichloromethane | |
With 10-methyl-9,10-dihydroacridine In acetonitrile at 24.9℃; | ||
With lithium hydroxide monohydrate; calcium(II) chloride; zinc Reagens 4: Soda; | ||
With diethyl ether; aluminum amalgam | ||
With sodium hydrogen sulphide | ||
With lithium hydroxide monohydrate; calcium(II) chloride; zinc | ||
With methanol; nickel Hydrogenation; | ||
With FERROUS SULFATE | ||
With hydrogen | ||
90 % Chromat. | With hydrazine In ethanol for 8h; Heating; | |
With methanol; copper atom; calcium(II) chloride; zinc for 4h; Heating; | ||
With hydrogen In various solvent(s) at 20℃; | ||
In methanol; lithium hydroxide monohydrate | R.21 REFERENCE EXAMPLE 21 REFERENCE EXAMPLE 21 To a solution of 4-nitrobenzylalcohol (4.59 g) in methanol (300 ml) was added copper chloride (I) (17.8 g) at room temperature, and then was gradually added potassium boron hydride (11.3 g) for 40 minutes. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=3/1) to give 4-aminobenzylalcohol (1.31 g) as pale yellow crystals. mp 53-55° C.; Elemental Analysis for C7 H9 NO; Calcd: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.43; H, 7.43; N, 11.49. IR (KBr) cm-1: 3375, 3219, 1614, 1514, 1470, 1259, 1041, 854, 827, 748, 509; 1 H NMR (200 MHz, CDCl3) δ: 3.50-3.85 (2H, br), 4.56 (2H, s), 6.68 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.4 Hz). | |
93 %Spectr. | With hydrogen In tetrahydrofuran at 20℃; for 3h; | |
With hydrogen In ethanol; lithium hydroxide monohydrate | 3.A Example 3; Benzo[c][l,2,5]oxadiazol-5-ylmethyl allyl(l-(((3S,4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate ; Step A; (4-Aminophenyl)methanol4-Nitrobenzyl alcohol (10.0 g, 65.3 mmol) was hydrogenated over 10% Pd/C (1 g, 50%H2O) in EtOH (150 mL). After the absorption of hydrogen was complete, the catalyst was filtered. The solution was concentrated under vacuum to provide the crude title compound that was used for next reaction without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.17 (d, J = 4.2 Hz, 2H), 6.67 (d, J = 4.2 Hz, 2H), 4.53 (s, 2H). | |
With hydrogen In ethanol | 3.A 4-Nitrobenzyl alcohol (10.0 g, 65.3 mmol) was hydrogenated over 10% Pd/C (1 g, 50% H2O) in EtOH (150 niL). After the absorption of hydrogen was complete, the catalyst was filtered. The solution was concentrated under vacuum to provide the crude title compound that was used for next reaction without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.17 (d, J = 4.2 Hz, 2H), 6.67 (d, J = 4.2 Hz, 2H), 4.53 (s, 2H). | |
With carbon monoxide; Au/TiO2-VS; lithium hydroxide monohydrate In ethanol at 25℃; for 2.5h; Autoclave; chemoselective reaction; | ||
With hydrogen In methanol at 20℃; for 1h; chemoselective reaction; | ||
With Sodium borohydride In lithium hydroxide monohydrate for 0.75h; Reflux; chemoselective reaction; | ||
99 %Chromat. | With hydrazine hydrate monohydrate In ethanol at 80℃; for 2h; Inert atmosphere; | |
With Adams’s catalyst; hydrogen In methanol at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; In dichloromethane; at 0℃; | Step B; 4-Acetamidobenzyl acetateTo a solution of (4-aminophenyl)methanol (2.0 g, 16.2 mmol) from step A and DMAP (0.40 g, 3.2 mmol)in DCM (50 mL) was added dropwise acetic anhydride (7.6 mL, 81.0 mmol) at 0 0C over 30 min. After stirring under nitrogen for 30 min, the solution was concentrated and extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (20% EA in PE) afforded the title compound as white solid (3.35 g, 100%). 1H NMR (CDCl3, 300 MHz): delta 7.51 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 5.05 (s, 2H), 2.16 (s, 3H), 2.08 (s, 3H). MS (ESI, Pos. 1.5 kV) m/z 230.0 (M+Na)+. |
100% | With dmap; In dichloromethane; at 0℃; for 1h;Inert atmosphere; | To a solution of (4-aminophenyl)methanol (2.0 g, 16.2 mmol) from step A and DMAP (0.40 g, 3.2 mmol)in DCM (50 mL) was added dropwise acetic anhydride (7.6 mL, 81.0 mmol) at 0 0C over 30 min. After stirring under nitrogen for 30 min, the solution was concentrated and extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (20% EA in PE) afforded the title compound as white solid (3.35 g, 100%). 1H NMR (CDCl3, 300 MHz): delta 7.51 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 5.05 (s, 2H), 2.16 (s, 3H), 2.08 (s, 3H). MS (ESI, Pos. 1.5 kV) m/z 230.0 (M+Na)+. |
92% | With Ni2B-Cu2O nanocomposite; In neat (no solvent); at 40℃; for 0.25h; | General procedure: For example, a mixture of aniline (1 mmol), Ni2B-Cu2O (54 mg), and acetic anhydride (1 mmol) was ground using a simple porcelain mortar and pestle for a minute at 40 C (in an oil bath). Reaction progress was monitored by TLC with nhexane:EtOAc:MeOH (5:3:1) as eluent. After reaction completion, the reaction mixture was cooled to room temperature, then 5 mL distilled water was added to the reaction vessel; subsequently, the reaction mixture was transferred to a flask (25 mL) equipped with a magnetic stirrer. The mentioned mixture was stirred vigorously for 2 min. Next, the product was extracted with dichloromethane (5 9 3 mL). Extraction solution was dried with anhydrous sodium sulfate then passed through a cotton filter. Evaporation of the solvent afforded pure acetanilide in 98 % yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;Heating / reflux; | To a solution of p-amino-benzylalcohol (1 g, 8.12 mmol, 1 eq) in 80 mL of anhydrous THF were added DIEA (1.4 mL, 8.12 mmol, 1 eq) and BoC2O (1.9 mL, 8.12 mmol, 1 eq). The mixture was heated to reflux overnight, then cooled down and evaporated under vacuum. The residue was dissolved in EtOAc. The organic layer was washed with a 0.1 N HCl solution, dried over MgSO4, filtered and evaporated under vacuum. The crude product was purified by <n="74"/>column chromatography on silica gel (Hex-EtOAc, 1:1, v/v) to give 1.85 g of product (quantitative yield): 1H NMR delta 0.1.49 (9H, s), 2.17 (IH, s), 4.53 (2H5 s), 6.83 (IH, s), 7.19 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.2 Hz); 13 C NMR delta 28.28, 64.54, 80.37, 118.49, 127.59, 135.31, 137.46, 152.72. |
99% | With sodium carbonate; In tetrahydrofuran; at 25℃; for 12h; | To a mixture of (4-aminophenyl)methanol (2.10 g, 17.1 mmol) in THF (30 mL) was added B0C2O (4.09 g, 18.8 mmol) and Na2C03 (2.17 g, 20.5 mmol), the reaction mixture was stirred at 25 C for 12 hours to give a white suspension. TLC (PE/EtOAc = 1/1) showed the reaction was completed. The mixture was filtered. The filter cake was washed with EtOAc (10 mL x2). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by washing with PE (40 mL) to give tert-butyl (4- (hydroxymethyl)phenyl)carbamate (3.8 g, yield: 99 %) as a white solid. (2040) NMR (400 MHz, DMSO-rie) d 1.48 (9H, s), 4.41 (2H, d, J= 4.8 Hz), 5.05 (1H, brs), 7.18 (2H, d, J= 8.4 Hz), 7.39 (2H, d, J= 8.4 Hz), 9.27 (1H, brs). |
98% | In dichloromethane; for 18h; | To a 250 mL round bottom flask was added (4-amino-phenyl)-methanol (4.13 g, 33.6 mmol), dichloromethane (50 mL) followed by di-tert-butyl dicarbonate (8.5 g, 36.9 mmol). The mixture was allowed to stir for 18 h under a nitrogen atmosphere. By TLC, a small amount of starting amine remained, which reacted during concentration by rotary evaporation. The product was purified by column chromatography (ethyl acetate : hexanes, 1:1) to yield (4- hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (7.36 g, 33.0 mmol, 98 %) as a white solid. |
98% | In neat (no solvent); at 80℃; for 0.166667h;Green chemistry; | General procedure: The reactions were carried out in a 50 mL RB flask under reduced pressure for 10 min at 80C unless reported differently. In a typical experiment, 5 mmol of amine was added to 5 mmol of BOC anhydride, and the reaction was allowed to proceed for 10 min. The desired product was obtained in a rotary evaporator under vacuum conditions. |
90% | In dichloromethane; | Novel UM101 analogues were synthesized (Schemes 3-5) and tested for interactions with p38a MAP kinase and biological activity. |
87% | With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 1.5h; | PREPARATION 15; Preparationof teri-buty 4-(chloromethyl)phenylcarbamate; A. To a stirred solution of 4-aminobenzyl alcohol ( 1.50 g. 12.18 mmol) in 1.4-dioxane (30 mL) was added sodium hydroxide (0.49 g. 12.2 mmol) in water (30 mL). The mixture was cooled to 0 0C. and di-/<?r/-butyl dicarbonate (2.93 g. 13.4 mmol) was added in portions. The resulting reaction mixture was stirred at ambient temperature for1.5 h. and diluted with ethyl acetate (75 mL). The organic layer was washed with 10% aqueous hydrochloric acid (2 * 35 mL) and water, dried over sodium sulfate, filtered and concentrated in vacuo to afford ?<?/Y-butyl 4-(hydroxymethyl)phenylcarbamate as a viscous yellowish liquid in 87% yield (2.36 g): 1H NMR (300 MHz. CDCl3) delta 7.37-7.26 (m. 4H). 6.52 (br s. I H). 4.63 (s, 2H). 1.52 (s. 9H); MS (ES+) m/z 246.3 (M + 23). |
83% | With triethylamine; In tetrahydrofuran; at 20 - 50℃; | A i00-mL, three-necked, round-bottomed flask, was equipped with a magnetic stimng bar, a retlux condenser, and a pressure-equalizing dropping funnel that was connected to a nitrogen flow line and charged with a solution of 97% di-tert-butyl dicarbonate (4.04 g, 18.5 nimol) in tetralydrofuran (30 mid). Amino benzyi alcohol (2.5 g, 20.3 mmol) was placed in the flask and suspended in tetrahydrofuran (65 mL) and 99% triethylamine (3.1 mL, 22 mmoi). The resultmg white suspension was cooled with an ice-water bath and the solution of di-tert-butyl dicarbonate was added dropwise over a period of 30 minutes. After 10 mm of additional stirring, the ice-water bath was removed and the suspension was stirred overnight at room temperature, then warmed at 50C for a further 3 hours. T he solvent was removed tinder reduced pressure and the residue partitioned between EtOAc (50 mL) and saturated aqueous bicarbonate solution (50 mL). The aqueous phase was extracted with three 50-ni. portions of EtOAc. The combined organic phases were dried with anhydrous MgSO4 and concentrated under reduced pressure to give 3.72 g (83% yield) of the product as a brown oil that was used without further purification. ?H NMR (as rotamers) (400 MHz, CDCh) 6 9.26 (s, I H), 8.64 (s, iH), 7.39 (.4H), 7.20 (4H), 5,75 (s, 1H), 5.05 (2H), 4.49 -4.35 (m, 4H), i.47 (s, 9H), 1.40 (s, 1H). |
82% | With triethylamine; In 1,4-dioxane; at 20℃; | Intermediate 10: tert-butyl 4-(hydroxymethyl)phenylcarbamateTo a solution of p-aminobenzyl alcohol (38,2 mmol) in 100 ml dioxane were added triethylamine (114 mmol) and di-tert-butyldicarbonate (42,0 mmol) was added in portions. The mixture was stirred overnight at room temperature. The solvent was evaporated. EtOAc was added and washed with 2N HCI, saturated NaHCO3 and brine solution. The organic layer was dried over Na2SO4 and evaporated to yield a brown oil.Yield: 82 %, MS (ESI) m/z 224.3 [M+H]1H-NMR (ODd3, 400 MHz) 51.54 (s, 9H), 4.65 (s, 2H), 6.54 (s, 1H), 7.22-7.43 (m, 4H). |
74% | With acetic acid; In tetrahydrofuran; water; at 20℃; for 18h;Inert atmosphere; | tert-Butyl (4-(hydroxymethyl)phenyl)carbamate 19. To a solution of ra-aminobenzyl alcohol (0.123 g, 0.0999 mmol) in AcOH (10% in water, 8 mL) was added a solution of di-feri-butyl dicarbonate in THF (1 M, 1.05 mL, 1 .05 mmol), and the reaction was stirred for 18 h at ambient temperature. Water (30 mL) was added, and the mixture was basified with a NaOH solution (2 M) to pH 14. The resulting mixture was extracted with Et20 (3 chi 30 mL). The combined organic layer was washed with water (2 x 1 5 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to afford boc-protected aminobenzyl alcohol 19 (0.166 g, 0.743 mmol, 74% yield) as a light yellow solid. [000219] NMR (600 MHz, CDC13) delta 7.34 (2H, d, J = 8.0 Hz), 7.28 (2H, d, J = 8.4 Hz), 4.62 (2H, s), 1 .52 (9H, s). [000220] 13C NMR (150 MHz, CDC13) delta 152.9, 138.0, 135.6, 128.0, 1 18.7, 65.1 , 31.3, 28.5. [000221] HRMS: Obsvd 246.1 102 [M + Na]+, Calcd for C12H17NNa03: 246.1 101. |
59% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; | To a solution of (4-aminophenyl)methanol (30, 8.0 g, 65.0 mmol) in THF (50 mL) were added Boc2O (21.3 g, 97.5 mmol) and DIEA (16.8 g, 130.0 mmol) at rt, and the resulting mixture was refluxed overnight. The reaction mixture was concentrated and purified by column chromatography (silica gel, eluted with 1:10 MeOH/DCM) to yield 31 (8.6 g, 59%) as a yellow solid. 1H NMR (400 MHz, CD3OD) delta 1.53 (9H, s), 4.54 (2H, s), 7.26 (2H, d, J = 8.4 Hz), 7.38 (2H, d, J = 8.4 Hz). MS (API): m/z 206.0 (M + H - H2O)+. |
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 6h; | A solution of 4-aminobenzyl alcohol (1.0 g) in dioxane (5 mL)/water (5 mL)/1N sodium hydroxide (8 mL) at 0 C. is treated with di-tert-butyl dicarbonate (2.65 g) in one portion. The mixture is warmed up to room temperature and stirred for 6 hours at ambient temperature. Most of the dioxane is removed under reduced pressure. The aqueous concentrate is then extracted twice with ethyl acetate and the combined organic extract is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and pumped under high vacuum to give 1.8 g product as a white solid. MS: m/z 224 (M+H)+. | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; | a) tert-Butyl N-(4-(hydroxymethyl)phenyl)carbamate. (4-Aminophenyl)methanol (1.23 g, 10 mmol) and diisopropylethylamine (2.6 mL, 15 mmol) was mixed with di-tert-butyl dicarbonate (2.62 g, 12 mmol) in dichloromethane (50 mL). The mixture was stirred at room temperature overnight. Ethyl acetate was added and the organic layer was washed with water, 1.0N HCl, saturated sodium carbonate, water, brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash column chromatography with Ethyl acetate/heptane (2:3) to give tert-butyl N-(4-(hydroxymethyl)phenyl) carbamate (2.16 g, 9.67 mmol). 1H NMR (CDCl-d) delta1.52 (s, 9H), 4.63 (s, 2H), 6.47 (bs, 1H), 7.30 (d, 8.5 Hz, 2H), 7.36 (d, 8.5 Hz,2H). | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; | a tert-Butyl N-(4-(hydroxymethyl)phenyl)carbamate (4-Aminophenyl)methanol (1.23 g, 10 mmol) and diisopropylethylamine (2.6 mL, 15 mmol) was mixed with di-tert-butyl dicarbonate (2.62 g, 12 mmol) in dichloromethane (50 mL). The mixture was stirred at room temperature overnight. Ethyl acetate was added and the organic layer was washed with water, 1.0N HCl, saturated sodium carbonate, water, brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash column chromatography with Ethyl acetate/heptane (2:3) to give tert-butyl N-(4-(hydroxymethyl)phenyl)carbamate (2.16 g, 9.67 mmol). 1H NMR (CDCl-d) delta1.52 (s, 9H), 4.63 (s, 2H), 6.47 (bs, 1H), 7.30 (d, 8.5 Hz, 2H), 7.36 (d, 8.5 Hz,2H). | |
at 20℃; | To 4.97 g (40.35 mmol) of 4-aminobenzylalcohol dissolved in 30 mL of was added 9.69 g (44.39 mmol) of di-tert-butyl dicarbonate. The mixture was stirred at room temperature overnight, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated to provide 8.4 g t-butyloxycarbonyl-protected 4-aminobenzyl alcohol, as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | The specific process is: 4-aminobenzyl alcohol (1.48g, 12mmol) with 4N sulfuric acid (15mL) is dissolved, and cooled to 0 C. then sodium nitrite (1.66 g, 24 mmol) was dissolved in water (10 mL) and dissolved, and then added dropwise. after controlling the temperature at 0 C for 30 min. sodium azide (2.34 g, 36 mmol) was dissolved in water (10 mL), and added dropwise to the above reaction solution, and slowly warmed to room temperature for 1 h. After completion of the reaction, the mixture was extracted with ethyl acetate. The organic phase was combined, and the organic phase was washed with a saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. Purified with petroleum ether / 0-10% ethyl acetate)The product was obtained as a yellowish solid, 4-azidobenzyl alcohol, yield 90%. | |
90% | (4-Aminophenyl)methannol 6a (2.00 g, 16 mmol) was dissolved in 6MHCl (16 mL). Sodium nitrate (1.67 g, 24 mmol) was added slowly at 0 C. After stirring at sametemperature for 30 min, sodium azide (4.23 g, 65 mmol) was added slowly at 0 C. The reaction mixturewas stirred at same temperature for 30 min then extracted with Et2O twice. The organic layer was washedwith saturated aq. NaHCO3 and saturated aq. NaCl, dried over MgSO4, filtrated and concentrated. Theresidue was subjected to silica column chromatography (AcOEt : hexane = 1 : 1) to afford yellow oil(2.17 g, 90%). IR (neat, cm-1) 2154. 1H-NMR (CDCl3) delta: 7.24 (2H, d, J = 8.6 Hz), 6.94 (2H, d, J = 8.6Hz), 4.52 (2H, s), 3.27 (1H, s). 13C-NMR (CDCl3) delta: 139.0, 137.4, 128.3, 118.8, 64.1. ESI-TOF-MS:[M+H]+ calculated for C7H7N3O 150.0667, found 150.0663. | |
88.5% | Dissolve p-aminobenzyl alcohol (1.20 g, 9.7 mmol) in distilled water (3 mL).Concentrated hydrochloric acid (36% HCl, 3 mL) was added,An aqueous solution (10 mL) of sodium nitrite (NaNO2, 0.69 g, 10.0 mmol) was slowly added dropwise at 0C.After 30 min, a solution of sodium azide (NaN3, 0.78 g, 12.0 mmol) in water (10 mL) was slowly added dropwise.Then stir at room temperature for 14-16 hours, extract three times with ethyl acetate, dry, and spin down to remove ethyl acetate.The obtained p-azidobenzyl alcohol (1.32 g, yield 88.5%) was used directly for the next reaction. |
86% | To a solution of 4-aminobenzylalcohol (300 mg, 2.44 mmol) in 5 mL of 10% HCl aqueous solution wasadded NaNO2 (201 mg, 2.92 mmol) in 3 mL aqueous solution at 0 C andstirred for 30 min. Then NaN3 (190 mg, 2.92 mmol) in 3 mL aqueoussolution was added at 0 C and stirred for another hour. The reaction mixturewas warmed to 25 C, diluted with ethyl acetate, washed with water and brine,dried over Na2SO4, concentrated in vacuo and subjected tosilica gel chromatography. A yellow oil 3(315 mg, 86% yield) was obtained by silica gel column chromatography using Petroleum ether/EtOAc (5:1, v:v) as eluent. 1HNMR (500 MHz, CDCl3)delta 7.23 (d, J= 8 Hz, 2H), 6.93 (d, J = 8.5 Hz,2H), 4.51 (s, 2H), 2.04 (s, br, 1H). | |
86% | To a solution of 4-aminobenzyl alcohol (300 mg, 2.44 mmol) in 5 mL of 10% HCl aqueous solution was added NaNO2 (201 mg, 2.92 mmol) in 3 mL aqueous solution at 0 o C and stirred for 30 min. Then NaN3 (190 mg, 2.92 mmol) in 3 mL aqueous solution was added at 0 o C and stirred for another hour. The reaction mixture was warmed to 25 o C, diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, concentrated in vacuo and subjected to silica gel chromatography. A yellow oil 3 (315 mg, 86% yield) was obtained by silica gel column chromatography using Petroleum ether/EtOAc (5:1, v:v) as eluent. 1H NMR (500 MHz, CDCl3) d 7.23 (d, J 8 Hz, 2H), 6.93 (d, J 8.5 Hz, 2H), 4.51 (s, 2H), 2.04 (s, br, 1H). | |
85% | 2.15g (17.5mmol) of 4-aminobenzyl alcohol was added to 20mL of 10% HCl aqueous solution at 0C, followed by addition of 1.45g (21.0mmol, 1.2equiv) sodium nitrite dissolved in dry 10mL CH2Cl2. After the mixture was stirred at 0C for 1h, 4mL of sodium azide (1.88g, 28.9mmol) aqueous solution was added drop-wise and stirred overnight. Then, the mixture was quenched with brine and extracted with ethyl acetate (100mL×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. Finally, the crude product was purified by flash chromatography (petroleum/ethyl acetate=4:1) to give a yellow oil (2.21g, 85%). 1H NMR (400MHz, DMSO): delta=6.95 (d, J=8Hz, 2H), 6.50 (d, J=8Hz, 2H), 4.92 (s, 2H), 4.79 (t, J=8Hz, 1H), 4.28 (d, J=8Hz, 2H) (Fig.S3). 13C NMR (100MHz, DMSO): delta=145.97, 131.13, 128.78, 115.20, 65.16 (Fig.S4) | |
84% | Compound 6 was synthesized from the corresponding aminated compound. For this a solution of 4-aminobenzyl alcohol (2.15 g, 17.5 mmol) were dissolved in THF (25 mL) and dropped into a rounded bottom flask cooled at 4 oC containing an aqueous solution of H2SO4 (4.8 mL 98%, in 60 mL of water). -Caution for preparing the H2SO4 solution slowly add concentrated acid into cooled water and not vice versa - Over the obtained acid solution of 4 amino benzyl alcohol in ice bath, a solution of NaNO2 (1.45g, 21 mmol) dissolved in water (10 mL) was added. The mixture was led to react 1 h in ice bath. Passed that time NaN3 (1.8 g, 28.9 mmol) dissolved in 5 mL water was added to the solution. The mixture was led to react overnight. Passed that time 4-azidobenzyl alcohol was collected by three liquid-liquid extraction processes using dichloromethane (100 mL). Fractions were collected dried over anhydrous Na2SO4, concentrated and purified by flash column chromatography (DCM: MetOH 19:1). Yield 84%. | |
81% | A stirred solution of 4-aminobenzyl alcohol 1 (4.0 g, 32.5 mmol) in 60 ml 5M hydrochloric acid, was cooled to 4 C. and a solution of sodium nitrite (2.48 g, 35.9 mmol) in 20 ml water was added dropwise in 30 min. Sodium azide (8.50 g, 130.7 mmol) was added in small portions over 30 min. with vigorous stirring. The reaction temperature was kept under 5 C. After stirring for 1.5 hour at 4 C. the reaction mixture was poured into ice water and basified (NaHCO3) to pH 8 (be aware of acid-base reaction). The water layer was extracted with EtOAc and washed with water (2×). The EtOAc layer was dried (MgSO4) and evaporated. Light petroleum benzine was poured on the residue, stirred for 30 min. and kept at 0 C. overnight affording a cream-colored suspension. After filtration the residue was washed with 5 ml light petroleum benzine yielding 2 (3.93 g, 26.3 mmol, 81%) as a cream-colored powder (photosensitive). 1H NMR, deltaH (CDCl3) 1.72 (1H, s, OH), 4.67 (2H, s, CH2), 7.02 (2H, d, J=8.48, aromatic), 7.35 (2H, d, J=8.67, aromatic). | |
78% | 4-aminobenzyl alcohol (1 g, 8.12 mmol) was dissolved in 5 mL of 5M hydrochloric acid solution,A solution of sodium nitrite (840 mg, 12.18 mmol, dissolved in 20 mL of deionized water) was added dropwise to the solution. The mixture was added dropwise within 30 minutes. The reaction mixture was vigorously stirred in an ice-water bath.Sodium azide (2.1 g, 32.3 mmol) was added portionwise to the reaction system, and the resulting mixture was stirred at room temperature overnight. After the reaction is complete,The residue was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated.The crude product was isolated and purified by silica gel column chromatography (EA:PE=1:3, volume ratio) to give 950 mg of a yellow oily liquid in a yield of 78.0%. | |
General procedure: To a solution of particular aromatic amine in 1,4-Dioxane (at the rate of 50 mg/ml) at -15.0 C, 5 equivalents of 2 M Sulphuric acid was added in small instalments while stirring. After 5 min 2 equivalents of 3 M sodium nitrite was added drop wise and after 30 min 3 equivalents of 3 M sodium azide was added drop wise carefully. Reaction was brought to room temperature and extracted with diethyl ether for at least three times. Organic layers were washed with saturated sodium bicarbonate solution two times, dried over anhydrous sodium sulphate and concentrated to a minimum volume under reduced pressure on Rotary evaporator without making use of heating from water bath. | ||
General procedure: To a solution of particular aromatic amine, 1:1 HCl-water was added in small instalments while stirring at 0C. After 10min, 4 equivalents of 3M sodium nitrite in water was added drop wise and after 30min 3 equivalents of 3M sodium azide and sodium acetate in water was added drop wise carefully keeping the reaction mixture at 0C or below (Scheme 2). After completion of addition, reaction was brought to room temperature and allowed to react for one more hour and finally extracted with diethyl ether for at least three times. Organic layers were washed with saturated sodium bicarbonate solution two times, dried over anhydrous sodium sulphate and concentrated to a minimum volume under reduced pressure on rotary evaporator. | ||
With sodium azide; sulfuric acid; sodium nitrite; at 0℃; | 100 ml of 2M H2SO4 solution, 39 g of 3-aminobenzyl alcohol or 4-aminobenzyl alcohol, 42 g of sodium nitrite and 42 g of sodium azide were added and stirred at 0 C to obtain Compound I-A. 15 g of compound I-A was dissolved in 150 ml of dichloromethane, 22 g of pyridinium chlorochromate was added, stirred at room temperature for 3 hours, concentrated by extraction, and recrystallized from 10 ml of ethanol to give compounds I-B. 2.9 g of compound I-B was added, 3.6 g of 3,4,5-trimethoxyaniline was added, and the compound I-C was pulverized by stirring at room temperature. 20 ml of anhydrous methylene chloride, 0.03 mol of triethylamine, 0.02 mol of aromatic ring acetyl chloride and 0.02 mol of compound I-C were added and the reaction was carried out to give azide-beta-lactam derivative I-1 to I-9. | |
(1) <strong>[623-04-1]4-Aminobenzyl alcohol</strong> (317.72 mg, 2.58 mmol) was dissolved in 8 mL of a 10% hydrochloric acid solution under N2.Sodium nitrite (NaNO2, 211.4 mg, 3.06 mmol) was dissolved in 3.2 mL of water.It was added dropwise to the above solution within 30 min. Sodium azide (NaN3, 200.7 mg, 3.08 mmol) was then added portionwise, and the mixture was stirred for 2 h.Extract with ethyl acetate (3 x 50 mL) and water (3 x 50 mL) and collect organic layer.Dry with anhydrous sodium sulfate (Na2SO4), filter,The filtrate was rotary evaporated on a rotary evaporator to give a yellow oily compound.4-azidobenzyl alcohol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With C39H53ClN2P2Ru; potassium methanolate; hydrogen; In tetrahydrofuran; at 20℃; under 38002.6 Torr; for 16h;Glovebox; Autoclave; | General procedure: In a glove box, add a ruthenium complex Il (0.75 mg, 0.001 mmol),Potassium methoxide (3.5 to 70 mg, 0.05 to 1 mmol), tetrahydrofuran (1 to 10 mL), and ester compounds (0.5 to 10 mmol).After sealing the autoclave, remove it from the glove box and fill it with hydrogen to the required pressure.The reaction vessel was stirred at room temperature for 16 to 24 hours.After slowly releasing excess hydrogen, the reaction solution was depressurized to remove the solvent, and the residue was purified by a short column of silica gel to obtain an alcohol compound.The results are shown in Table 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Preparation of 4-((tert-butyldimethyIsilyloxy)methyI)aniline; To a solution of (4-aminophenyl)methanol (3 g, 24.36 mmol) in DMF (85 mL) was added DMAP (0.982 g, 8.04 mmol) and triethylamine (4.07 mL, 29.2 mmol). Tertbutylchloro- dimethylsilane (4.04 g, 26.8 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered to remove the salt. The filtrate was concentrated to afford 7.9 g of a red solid, which was dissolved in EtOAc (200 mL), washed with water (100 mL), saturated ammonium chloride (2 x 50 mL), water (2 x 50 mL) and brine (50 mL), the organic layer was dried over Na2SO4. Filtration and concentration afforded 4- <n="153"/>((tertbutyldimethylsilyloxy)methyl)aniline (5.66 g, 23.84 mmol, 98% yield) as a red oil. LCMS (Table 1, Method a) R, = 3.10 min, m/z 238.19 (M+H)+; 1H NMR (400 MHz, DMSO-d6) delta ppm 6.94 (d, 2H), 6.51 (d, 2H), 4.95 (s, 2H), 4.49 (s, 2H), 0.87 (s, 9H), 0.03 (s, 6H). |
96% | With 1H-imidazole; In dichloromethane; at 20℃; for 1h; | To a solution of (4-Aminophenyl)methanol (1.50 g, 12.18 mmol) in CH2CI2 (20 ml.) was added TBDMSCI (1.84 g, 12.18 mmol) and imidazole (0.91 g, 13.40 mmol). After stirring for 1 h at room temperature, the solution was diluted with brine, and extracted with E-tOAc. The organic extract was dried (Na2SO4), filtered, and evaporated. The residue was purified by silica gel column chromatography with gradient of EtOAc (25-100%) in Hexane to afford 67 (2.76 g, 96%) as a light yellow oil. LRMS (ESI): (calc.) 237.4; (found) 238.2 (MH) + |
82% | With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.25h; | A- Aminobenzyl alcohol (1.5 grams, 12.18 mmol, 1 equivalent) and imidazole (830 mg, 12.18 mmol, 1 equivalent) were dissolved in DMF and cooled to 0 0C. Thereafter TBDMS-CI (1.836 grams, 12.18 mmol, 1 equivalent) was added and the reaction stirred for 15 minutes at room temperature. EtOAc was then added, the organic phase washed with saturated NH4CI and dried over MgSO4. Flash chromatography afforded the protected alcohol Compound A (2.36 grams, 82 % yield, CAS No. 131230-76-7). |
82% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 5h; | To a solution of 4-aminobenzyl alcohol (2.0g, 16.24mmol) in dry DMF (20mL) were added tert-butyldimethylsilyl chloride (3.67g, 24.35mmol) and imidazole (2.21g, 32.46mmol), the resulting mixture was further stirred for 5hat room temperature. The reaction mixture was then diluted with saturated brine solution and extracted with CH2Cl2. The organic layer was separated and washed with brine solution for several times, then dried over anhydrous Na2SO4, evaporated under vacuum, the obtained brown residue was purified by silica gel chromatography (petroleum ether-ethyl acetate), a brown oil was obtained (3.15g, 82%). 1H NMR (CDCl3, 400MHz) delta7.12 (d, 2H, J=8.4Hz), 6.67 (d, 2H, J=8.0Hz), 4.62 (s, 2H), 3.80 (brs, 2H), 0.91 (s, 9H), 0.08 (s, 6H). |
82.1% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 16h; | A solution of (4-aminophenyl)methanol (5.00 g, 40.6 mmol) in anhydrous DMF (10 mL) was added dropwise within 30 min to a stirred solution of tert-butyl-chloro-dimethyl- silane (7.34 g, 48.7 mmol) and imidazole (7.90 mL, 81.2 mmol) in anhydrous DMF (40 mL). After stirring at room temperature for 16 h, the reaction mixture was poured into water (400 mL) and extracted with CH2CI2 (3c100 mL). The combined organic layers were washed with water (2c100 mL) and dried over MgS04. After removing the volatiles in vacuo, the residue was purified by column chromatography (Si02, 0-25% EtOAc/hexanes) affording 4- [[tert-butyl(dimethyl)silyl]oxy methyl] aniline (7.91 mg, 33.3 mmol, yield: 82.1 %). |
With 1H-imidazole; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h; | Step 1; A solution of 4-aminobenzyl alcohol (1. 23g, 10 mmol) in DMF (10 mL) was treated with t-butyidimethylsilyl chloride (1.5 g, 10 mmol) and imidazole (820 mg, 12 mmol) as described in step 4 example 3. The crude product (1. 98g) was used without further purification. | |
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 12h; | 4-(tert-Butyl-dimethyl-silanyloxymethyl)phenylamine. To a solution of 4-aminobenzyl alcohol (3g) in DMF (10OmL) was added tert-butyldimethylsilyl chloride (1 equivalent) and imidazole (1 equivalent) and the reaction allowed to stir at RT for 12 hours. The reaction was reduced in vacuo and partitioned between DCM and H2O and the organics dried over magnesium sulfate and reduced in vacuo. Material purified by column chromatography eluting with 1:9 EtO Ac/petrol to 1:4 EtO Ac/petrol to give the title compound as a pale yellow oil (1.89g). 1HNMR (MeOH-d4) 7.98 (2H, d), 6.60 (2H, d), 4.50 (2H, s), 0.85 (9H, m), 0.00 (6H, m). | |
With 1H-imidazole; In tetrahydrofuran; at 20℃; for 1h; | 4-Aminobenzyl alcohol (5.00 g, 40.6 mmol) and imidazole (5.52 g, 81.2mmol) were dissolved in tetrahydrofuran (30 mL) and a solution of tert-butyldimethylchlorosilane (9.14 g, 60.9 mmol) in tetrahydrofuran (10 mL) was added thereto. After stirring the reaction mixture at room temperature for 1 hour, the reaction was stopped by addition of purified water and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 4-[(tert-butyldimethylsilanoyloxy)methyl]aniline (9.94 g). | |
With dmap; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Tert-butyldimethylsilyl chloride (2.02 g, 13.4 mmol) was added to a solution of (4-ami- nophenyl)methanol (1.5 g, 12.2 mmol), DMAP (491 mg, 4.02 mmol) and TEA (1.48 g,14.6 mmol) in DMF (15 mL) at room temperature and stirred at overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried (Na2SO4), filtered and then the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (EtOAc/petrol ether) to give IT-007 as light yellow oil. A solution of IT-007 (2.3 g, 9.7 mmol) and TEA(982 mg, 9.7 mmol) in DCM (5 mL) was added dropwise to a solution of methyl phosphorodichloridate (1.44 g, 9.7 mmol) in DCM (20 mL) at -78 C under Ar. The mixture was stirred at -78 C for 30 mm before L-alanine isopropyl ester hydrochloride (1.63 g, 9.7 mmol) was added. TEA (2.45 g, 24.3 mmol) was then added dropwise into the reaction mixture. After addition, the mixture was warmed to room temperature and stirredovernight. The reaction was quenched with water and extracted with DCM twice. The combined organic layers were dried (Na2SO4), filtered and then the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (EtOAc/petrol ether) to give IT-008 as a colourless oil. TBAF (1 M in THF, 6.5 mL, 6.5 mmol) was added to a solution of IT-008 (970 mg, 2.18 mmol) in THF (10 mL). The re20 action was heated to 40 C and stirred overnight then the solvent was removed invacuo. The residue was purified by silica gel column chromatography (EtOAc/petrol ether) to give IT-009 as colourless oil. DIAD (245 mg, 1 .21 mmol) was added dropwise to a solution of IT-009 (100 mg, 0.303 mmol), 2,4-dinitrophenol (111 mg, 0.606 mmol) and Ph3P (159 mg, 0.606 mmol) in THF (5 mL) at 0 C. After addition, the mixture wasstirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was directly purified by preparative-TLC (EtOAc) to give the title compound as a slightly yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In ethanol for 1.5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; isopropyl alcohol for 24h; Heating; Title compound not separated from byproducts.; | ||
With hydrogen In tetrahydrofuran at 60℃; for 18h; Autoclave; chemoselective reaction; | ||
With potassium formate In water at 80℃; for 12h; | 2.3 Catalytic Test General procedure: A 10 mL aqueous solution containing 25 mg Au:PVP nanoparticles (5 lmol of Au) and 420 mg HCOOK (5 mmol) was prepared in a two neck round bottom flask fitted with reflux condenser and placed in temperature controllable oil bath with a magnetic stirrer bar inside. A 0.5 mmol portion of substrate (substrate/catalyst = 100) was added to this solution either in pure form (for liquids) or as a ethyl acetate solution (2 mL). The reaction was continued at 80 °C with a stirring rate of 900 rpm for a specific amount of time. After a given amount of time (12 h), the reaction mixture was transferred to a conical flask and 10 mL of ethyl acetate was added, and the mixture was stirred for 20 min to extract the reactants and products. The ethyl acetate phase was analyzed in a Shimadzu gas Chromatograph (GC 14A) coupled with a FID detector and using a silica capillary column (RTX 1). For recycling experiments, the aqueous Au:PVP solution was phase separated and reused in next batch of reaction under identical set of conditions. |
With pyridine; hydrogen In water at 80℃; for 3h; Sealed tube; | Catalytic Reaction The selective hydrogenation for 4-nitrobenzaldehyde was carried out as follows: 33 mg of 4-nitrobenzaldehyde, 48 μL of pyridine, 5 mg of AuC, and3 mL of water were added to a high pressure reactor. The reactor was sealed, stirred at 500 rpm, and incubated at 80 C with oil bath and 1.6 MPa H2. After the reaction was finished (3 h),the reactor was cooled to room temperature. The suspension was extracted with 10 mL of ethyl acetate for three times. The catalysts were separated with filtration. The solution was dried with anhydrous sodium sulfate and the solvent was removed through rotary evaporation. The product was analyzed by high performance liquid chromatography (HPLC, 6130 MSD,Agilent, Santa Clara, CA, USA), mobile phase A is the aqueous phase (containing 0.6% acetic acid and 0.3% triethylamine);mobile phase B is methanol. The flow ratio was VA: VB = 2:1;the flow rate was 0.8 mL/min; the detection wavelength was250 4 nm; and the injection volume was 3 μL. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With Co3O4 nanoparticles; at 20℃; for 0.2h;Green chemistry; | General procedure: In a round-bottomed flask (25 mL) equipped with a magnetic stirrer, a mixture of aniline (0.093 g, 1 mmol) and Co3O4 (0.006 g) was prepared. Acetic anhydride (0.102, 1 mmol) was then added to the reaction mixture and stirring was continued at room temperature for 3 min. The progress of the reaction was followed by TLC. After the reaction completion, the products was extracted with EtOAc and filtered to remove Co3O4. The organic solvent was then washed with H2O (2 x 10 mL) and saturated NaHCO3 solution and then dried over anhydrous Na2SO4. The solvent was removed under vacuum to afford the pure product. |
91% | In neat (no solvent); at 20℃; for 0.1h; | General procedure: Alcohol, phenol, and/or amine (1 mmol) were added to amixture of the ZnAl2O4SiO2 nanocomposite (100 mg) andacetic anhydride (1 mmol). The mixture was stirred at 75 C(for alcohols and phenols) or at room temperature (for amines)for a time. The progress of the reaction was monitored by TLCand/or GC-MS. When the reaction was completed, ethyl acetate(10 mL) was added and the mixture was filtered to separate offthe catalyst. The catalyst was washed twice with 7.5 mL ethylacetate. The combined organic phases were washed with a10% solution of NaHCO3 and then dried over MgSO4. The solventwas removed to yield the product. If further purificationwas needed, the product was passed through a short column ofsilica gel. All products were characterized on the basis ofGC-MS, FT-IR, and 1H-NMR spectral data by comparing thesespectra with those of standard samples or literature data. |
91% | In water; at 50℃; for 0.15h; | General procedure: In a round-bottom flask (10 mL) equipped with a magnetic stirrer, a mixture of PhNH2(1 mmol, 0.093 g) and H2O(3 mL) in oil bath (50 C) was prepared. Magnetically recyclable nanoparticles of Fe3O4/Cu (0.05 mmol) was then added, and the mixture was stirred for 1 min under oil bath conditions. Addition of Ac2O(1 mmol, 0.102 g) to the prepared mixture was followed by stirring for 3 min at 50 C. After completion of the reaction, the copper nanocatalyst was separated by an external magnet and the mixture was extracted with EtOAc (3 × 8 mL). Organic layers were then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure affords the pure acetanilide in 95% yield (0.128 g, Table 2, entry 1). |
In ethanol; water; at 70℃; | General procedure: In a round-bottom flask (25 mL), a solution of nitrobenzene (0.123 g, 1 mmol) in H2O-EtOH (1.5:0.5 mL) was prepared. Magnetically, nanoparticles of NiFe2O4(at)Cu (0.15 g) were added, and the resulting mixture was stirred for 5 min. Afterward,NaBH4 (0.094 g, 2.5 mmol) was added and the resulting mixture was continued to stirring for 1 min at 70 C. After reduction of nitrobenzene to aniline (monitored by TLC), Ac2O (0.204 g, 2 mmol) was added and the resulting mixture was stirred for 1 min at 70 C. The nanocatalyst was separated by an external magnet, and the mixture was extracted with EtOAc (3 × 5 mL). The organic layer was dried over anhydrous Na2SO4. Evaporation of the solvent affords the pure acetanilide in 95% yield (0.128 g, Table 3,entry 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; di-<i>tert</i>-butyl dicarbonate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.8% | With silica-supported Jones reagent In dichloromethane for 0.035h; | |
75% | With potassium hydroxide In 1,3,5-trimethyl-benzene at 160℃; for 24h; Inert atmosphere; | 2.4. General procedure for dehydrogenativeoxidation of alcohols General procedure: 1 mmol of alcohol, 2 mmol(112 mg)potassium hydroxide and 30 mg of prepared catalyst(MnFe-S-Ag) were mixed in areaction flask and 2 mL mesitylene was also added. The mixture was stirred for24 hours at 160°C under argon atmosphere.Progress of reaction was monitored using TLC analysis. When the reactionwas considered complete, catalyst was collected with a permanent magnet. Thensolvent was evaporated under reduced pressure. Water (10 mL) was added to theresulting mixture to dissolve salts. The starting material was removed toorganic layer, with extraction of the reaction mixture with EtOAc(3×10 mL).Subsequently, the aqueous layer was acidified to pH 5-6 with a 20% HClsolution(2-5 mL). The target acid was generated as a white to yellowprecipitate. Then it was extracted to EtOAc(3×10 mL) and the crudeproduct was obtained after evaporation of the organic solvent and it wasfurther purified by recrystallization if necessary. |
67% | Stage #1: 4-aminobenzenemethanol With C27H29BrFIrN2O; potassium hydroxide In toluene for 10h; Inert atmosphere; Reflux; Stage #2: With hydrogenchloride In water |
10% | Stage #1: 4-aminobenzenemethanol With ((CH3C6H4CH(CH3)2)RuI(C6H4NC3H2NCH3)); potassium hydroxide In m-xylene for 6h; Schlenk technique; Reflux; Inert atmosphere; Stage #2: With hydrogenchloride In water; m-xylene Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.06% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 25℃; for 8h;Darkness; | To a solution of Compound 2 (7.00 g, 18.70 mmol, 1.00 eq) in DCM (80.00 mL) and MeOH (40.00 mL) was added (4-aminophenyl)methanol (2.53 g, 20.56 mmol, 1.10 eq) and EEDQ (9.25 g, 37.39 mmol, 2.00 eq) in the dark. And the mixture was stirred at 25 C for 8 hr. LC-MS showed Compound 2 was consumed completely and one main peak with desired MS was detected. The resulting reaction mixture was concentrated under reduced pressure to remove the solvent to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 120 g SepaFlash Silica Flash Column, Eluent of 0-10% MeOH/DCM 85 mL/min). Compound 3 (7.00 g, 14.60 mmol, 78.06% yield) was obtained as a white solid. |
78.06% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 25℃; for 8h;Darkness; | General procedure: To a solution of Compound 2 (7.00 g, 18.70 mmol, 1.00 eq) in DCM (80.00 mL) and MeOH (40.00 mL) was added (4-aminophenyl)methanol (2.53 g, 20.56 mmol, 1.10 eq) and EEDQ (9.25 g, 37.39 mmol, 2.00 eq) in the dark. And the mixture was stirred at 25 C for 8 hr. LC-MS showed Compound2 was consumed completely and one main peak with desired MS was detected. The resulting reaction mixture was concentrated under reduced pressure to remove the solvent to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 120 g SepaFlash Silica Flash Colunm, Eluent of 0-40% MeOH/DCM 85 mL/min). Compound 3 (7.00 g, 14.60 mmol, 78.06% yield) was obtained as a white solid. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane;Darkness; | Compound E- 11-4: tert-butyl ((5)-i -(((5)-i -((4-(hydroxymethyl)phenyl) amino)- 1 -oxo-5-ureidopentan-2-yl)amino)-3 -methyl-i -oxobutan-2-yl)carbamate Compound E-11-3 (5g, 13.4 mmol, 1 eq.) was dissolved in a mixture of dry DCM (65 ml) and dry MeOH (35 ml). (4-aminophenyl)methanol (1.81 g, 14.7 mmol,1.1 eq.) and N-Ethoxycarbonyl-2-ethoxy-i,2-dihydroquinoline (EEDQ - 6.60 g, 26.7 mmol, 2 eq.) were added and the mixture stirred in the dark overnight. The solventswere evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 5.2 g (73 %) of compound E-11-4 as an off-white solid. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane;Darkness; | Compound E-ll-4: tert-butyl ((5)-l-(((5)-l-((4-(hydroxymethyl)phenyl) amino)- 1 -oxo-5-ureidopentan-2-yl)amino)-3-methyl- 1 -oxobutan-2-yl)carbamate Compound E-ll-3 (5g, 13.4 mmol, 1 eq.) was dissolved in a mixture of dry DCM (65 ml) and dry MeOH (35 ml). (4-aminophenyl)methanol (1.81 g, 14.7 mmol, 1.1 eq.) and N-Ethoxycarbonyl-2-ethoxy-l ,2-dihydroquinoline (EEDQ - 6.60 g, 26.7 mmol, 2 eq.) were added and the mixture stirred in the dark overnight. The solvents were evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 5.2 g (73 %) of compound E-ll-4 as an off-white solid. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane;Darkness; | Compound E-ll-3 (5g, 13.4 mmol, 1 eq.) was dissolved in a mixture of dry DCM (65 ml) and dry MeOH (35 ml). (4-aminophenyl)methanol (1.81 g, 14.7 mmol, 1.1 eq.) and N-Ethoxycarbonyl-2-ethoxy-l ,2-dihydroquinoline (EEDQ - 6.60 g, 26.7 mmol, 2 eq.) were added and the mixture stirred in the dark overnight. The solvents were evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 5.2 g (73 %) of compound E-ll-4 as an off-white solid. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane;Darkness; | Compound E-11-4: tert-butyl ((S)-1-(S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate Compound E-11-3 (5 g, 13.4 mmol, 1 eq.) was dissolved in a mixture of dry DCM (65 ml) and dry MeOH (35 ml). (4-aminophenyl)methanol (1.81 g, 14.7 mmol, 1.1 eq.) and N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ -6.60 g, 26.7 mmol, 2 eq.) were added and the mixture stirred in the dark overnight. The solvents were evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 5.2 g (73%) of compound E-11-4 as an off-white solid. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane;Darkness; | Compound E-11-3 (5g, 13.4 mmol, 1 eq.) was dissolved in a mixture of dry DCM (65 ml) and dry MeOH (35 ml). (4-aminophenyl)methanol (1.81 g, 14.7 mmol, 1.1 eq.) and NEthoxycarbonyl-2-ethoxy-i,2-dihydroquinoline (EEDQ - 6.60 g, 26.7 mmol, 2 eq.) were added and the mixture stirred in the dark overnight. The solvents were evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 5.2 g (73 %) ofcompound E-11-4 as an off-white solid. |
71% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 24h; | A solution of Boc-Val-OSu (iO.0 g, 3i.8 mmol, ieq.) in THF (50 mE) was added to a solution of H-Cit-OH (5.85 g, 33.4 mmol, i.05 eq.) and NaHCO3 (2.94 g, 34.9 mmoE, i.i eq.) in THF (50 mE) and H20 (iOO mE). The mixture was stirred at room temperature for 72 hours and the THF was evaporated under reduced pressure. The pH was adjusted to 3 with citric acid to precipitate a white gum. This was extracted with iO% IPAethylacetate (8xi50 mE), the combined extracts were washed with brine (300 mE) and dried (Mg504). Evaporation under reduced pressure gave a white foam which was dried under reduced pressure for i8 hours. The foam was suspended in ether with sonication followed by filtration to give the product as a fine white powder (iO.6 g, 89%).Aportion ofthis material (7.2 g, i9.2 mmol, i eq), p-aminobenzyl alcohol (2.6 g, 2i.i5 mmol, i.i eq.) and EEDQ (9.5 g, 38.5 mmol, 2.0 eq.) in DCM/MeOH (iOO mE/SO mE) were stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residual gum was triturated with ether with sonication, the resulting product was collected by filtration and dried under reduced pressure to give the product 82 as a white solid (6.6 g, 7i%). Analytical Data: RT 2.42 mm; MS (ES) mlz (relative intensity) 479.8 ([M+i], 60), MS (ES-) mlz (relative intensity) 477.6 ([M-H]), 90). |
70% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; | Boc-Val-Cit (1 g. 2.67 mmol, leq) and p-aminobenzyl alcohol (362 mg, 2.94 mmol, 1.1 eq) in 2:1 DCM/MeOH (26 mL/13 mL) were treated with EEDQ (1.32 g, 5.34 mmol, 2 eq). The mixture was stirred in the dark at room temperature overnight The solvents were removed <n="76"/>under vacuum and the resulting solid residue was triturated with 10 mL of ethyl ether. The solid was collected by filtration and washed with ethyl ether to yield the product (900 mg, 70%): 1H NMR (CD3OD) delta 0.93 (3H, d, J = 7.0 Hz), 0.97 (3H, d, J = 7.0 Hz)3 1.44 (9H, s), 1.49-2.06 (5H, m), 3.07-3.29 (2H, m), 3.91 (IH, d, J = 6.7 Hz), 4.50-4.55 (3H, m), 7.29 (2H, d, J = 8.5 Hz), 7.54 (2H, d, J = 8.5 Hz), 8.22 (IH, d, J = 7.3 Hz); 13C NMR (CD3OD) delta 18.64, 19.85, 27.84, 28.75, 30.61, 31.92, 40.28, 54.90, 54.99, 61.73, 64.78, 80.62, 121.09, 128.44, 138.47, 138.55, 158.01, 162.11, 172.00, 174.42, 174.52. |
57.8% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 25℃; for 12h; | To a solution of compound 3.1 (10.0 g, 26.71 mmol, 1 eq) in DCM (40 mL) and MeOH (20 niL) was added EEDQ (13.2 g, 53.41 mmol, 2 eq) and (4-aminophenyl)methanol (3.95 g, 32.05 mmol, 1.2 eq). The mixture was stirred at 25 C for 12 hr. LC-MS showed compound 3.1 was consumed completely and one main peak with desired MS was detected. TLC indicated compound 3.1 was remained, and one major new spot with lower polarity was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 330 g SepaFlash Silica Flash Column, Eluent of 0-15% EtOAc/PE gradient 100 mL/min). Compound 3.2 (7.4 g, 15.43 mmol, 57.8% yield) was obtained as a white solid. MS (ESI) m/z: calcd. for [M+H]+, 480.27; found, 480.1 (M/l+H)+. |
52% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 30℃; for 16h;Darkness; | To a solution of compound 2 (30 g, 80 mmol) in DCM (300 mL) and MeOH (150 mL) was added 4- aminophenyl methanol (1 1 g, 88 mmol) and EEDQ (40 g, 160 mmol) in the dark. The mixture was stirred at 30 C for 16 hr. TLC (DCM:MeOH = 10/1, Rf= 0.43) indicated compound 2 was consumed completely and many new spots formed. The reaction was clean according to TLC. The resulting reaction mixture was concentrated to give a residue, which was purified by flash silica gel chromatography (ISCO; 330 g x 3 SepaFlash Silica Flash Column, Eluent of 0-20% MeOH/Dichloromethane 100 mL/min). Compound 3 (20 g, 52% yield) was obtained as a white solid. |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 18h;Inert atmosphere; | 100074] Boc-Val-Citrulline (ic, 12.93 g, 34.57 mmol) and 4-Aminobenzyl alcohol (PABOH,4.683 g, 38.03 mmol) in CH2C12 (250 mL) and MeOH (125 mL) at room temperature were treated with EEDQ (12.83 g, 51.86 mmol). The reaction mixture was stirred under nitrogen at room temperature for 18 hours. The solvents were removed and the white solid residue was triturated with ether. The solid was collected by filtration , washed with ether and concentrated under reduced pressure to give Boc-Val-Cit-PABOH (id). ?H NMR (500 MHz, DMSO-d6): & 7.54 (d, 2H), 7.29 (d, 1H), 4.52 (s, 2H), 3.90 (d, 1H), 3.19 (m, 1H), 3.10 (m, 1H), 1.51-20.6 (m, 511), 1.44 (s, 911), 0.97 (d, 3H), 0.92 (d, 3H). MS (M+1 ): 480.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 88% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 48h;Darkness; | DCM/MeOH=2/1 mixed solvent 60 ml was added to the reaction flask, followed by addition of Fmoc-vc2g (4.2 mmol) and1.04 g (2 eq) of PABOH was added. After stirring the dissolved portion, 2.0 g (2 eq) of EEDQ was added. The reaction system is protected from light at room temperatureStir the reaction for 2.0 days. After completion of the reaction, the mixture was concentrated under reduced pressure at 40C to give a white solid. Collect white solids and add methyl tert-butylEthyl ether (100 ml) was stirred and filtered, and the filter cake was washed with methyl tert-butyl ether. The resulting white solid was dried at 40 C under reduced pressure to give 2.2 g.About 88% |
88% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 48h;Darkness; | Add 60 ml of DCM/MeOH=2/1 mixed solvent to the reaction flask.Add Fmoc-vc 2g (4.2mmol) andPABOH 1.04g (2eq),After stirring the dissolved fraction, EEDQ 2.0 g (2 eq) was added.The reaction system was stirred at room temperature for 2.0 d in the dark.After completion of the reaction, concentration under reduced pressure at 40 C gave a white solid.The white solid was collected and stirred with 100 ml of methyl tert-butyl ether.Filtered, the filter cake was washed with methyl tert-butyl ether.The obtained white solid was dried under reduced pressure at 40 C to give 2.2 g.The yield is about 88%. |
87% | With 1-bromo-2,3,4-tri-O-acetyl-alpha-D-glucuronic acid methyl ester; In methanol; dichloromethane; at 20℃; for 48h;Darkness; | The Fmoc-Val-Cit 4 (1.0 g, 2.01 mmol) and p-aminobenzyl alcohol (492 mg, 4.0 mmol) were dissolved in a 1 : 1 solution of dichloromethane / methanol (30 mL). To this mixture was added N-Ethoxycarbonyl-2-ethoxy- 1 ,2-dihy droquinoline (992 mg, 4.0 mol). The reaction flask was wrapped in foil and the hood lights were turned off, while the reaction wns stirred at room temperature for 48 hours. (1046) [0558] The reaction mixture was evaporated to dryness and the resulting solid was titurated with ether. The suspension was stirred overnight in ether, then filtered to give a yellow solid. The solids were again washed with ether to give 990 mg for a 87% yield. MS (ESI): mie 572.66 (Mi l) , 573, (M + Na)+, 595. |
85% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 36h;Darkness; Inert atmosphere; | Fmoc-Val-Cit-PABOH 2. To a solution of Fmoc-protected dipeptide 1 (0.30 g, 0.60 mmol) in CH2Cl2/MeOH (2: 1 , 9 mL) was added P-aminobenzyl alcohol (0.12 g, 0.98 mmol ) and EEDQ (0.24 g, 0.98 mmol), and the reaction mixture was stirred in the dark for 1.5 d. The solvents were evaporated, and the resultant was triturated with Et20 (25 mL). The resulting suspension was sonicated for 20 min and left to stand for 30 min. The crude product was collected by filtration and then purified by flash chromatography using a pre-packed 50 g silica column [solvent A: MeOH; solvent B: CH2C12; gradient: 0%A / 100%B (1 CV), 0%A / 100%B -? 20%A / 80%B (10 CV), 20%A / 80%B (2 CV); flow rate: 40 mL/min; monitored at 254 and 280 nm] to afford Fmoc-protected compound 2 (0.31 g, 0.51 mmol, 85% yield) as a brown solid. [000188] NMR (500 MHz, DMSO-d6) 6 10.00 (1 H, s), 8.13 (1 H, d, J = 7.7 Hz), 7.92 (2H, d, J = 7.5 Hz), 7.81 - 7.71 (2H, m), 7.57 (2H, d, J= 8.4 Hz), 7.49 - 7.40 (3H, m), 7.35 (2H, t, J= 7.4 Hz), 7.26 (2H, d, J = 8.3 Hz), 5.99 (1 H, t, J = 6.5 Hz), 5.43 (2H, s), 5.12 (1 H, t, J= 5.6 Hz), 4.45 (2H, d, J= 5.4 Hz), 4.32 (1H, d,J= 10.1 Hz), 4.29 - 4.19 (3H, m), 4.00 - 3.88 (1H, m), 3.12 - 2.91 (2H, m), 2.09 - 1.94 (1H, m), 1.80-1.31 (4H, m), 0.90 (3H, d, .7=6.6 Hz), 0.88 (3H, d,J=6.7 Hz). [000189] I3C NMR (125 MHz, DMSO-d6) delta 171.7, 170.9, 159.3, 156.6, 144.4, 144.2, 141.2, 138.0, 137.9, 128.1, 127.6, 127.4, 125.8, 120.6, 119.3, 66.2, 63.1, 60.6, 47.2,30.9,30.0, 27.3, 19.7, 18.8, 15.0. |
82% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; at 20℃; for 36h; | Fmoc-val-cit (1 eq),Add 2 eq of p-aminobenzyl alcohol (2 eq) to DMC / MeOH (2: 1), add EEDQ (2 eq) and shake for 1.5 days at room temperature.After completion of the reaction, the solvent is dried and precipitated with ether. Repeat after filtering with Ether. Yield: yellow solid 82%. |
80% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In water; ethyl acetate; N,N-dimethyl-formamide; at 0 - 5℃; | Fmoc-Val-Cit (1 eq.), HATH (1.4 eq.) were solubilized in a mixture of anhydrous N,N-Dimethylformamide (9.5 vol.) and Ethyl acetate (5 vol.) at 20C. The reaction mixture was then cooled to 0-5C. Separately, a solution of 4-Aminobenzyl alcohol (1.5 eq.) in Ethyl acetate (2 vol.) and anhydrous N,N-Dimethylformamide (0.5 vol.) was prepared. A solution of N,N-Diisopropylethylamine (1.4 eq.) in Ethyl acetate (2 vol.) was also prepared. Water (1 vol.) was added to the cooled Fmoc-Val-Cit/HATU solution before adding the 4- Aminobenzyl alcohol solution quickly. Immediately thereafter, the DIPEA solution was added over 25-35 minutes. The reaction mixture was stirred at 0-5C for 1-2 hours until reaction was complete. Pre-chilled Methyl tert-butyl ether (20 vol.) was then added over 10 minutes and the resulting mixture was stirred for 1-3 hours. Solids were filtered, washed and dried under vacuum. Solids were re-slurried in Acetonitrile (20 vol.), filtered, washed and dried under vacuum (80% yield). MS: m/e 602 (MH)+, 624 (M+Na)+. |
77% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 40℃; | Step 3 Synthesis of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (92) To the suspension of compound 90 (70 g, 0.141 mol) in DCM/MeOH (1 L/500 mL) was added compound 91 (34.7 g, 0.282 mol) followed by EEDQ (69.7 g, 0.282 mol). The mixture was stirred at 40 C. overnight. The reaction mixture was filtered and the wet cake was suspended in EtOAc/TBME (500 mL/200 mL) and stirred for 30 min, then filtered. The solid was washed with EtOAc/TBME to provide compound 92 as off-white solid 65 g (77%). 1H NMR (400 MHz, DMSO-d6) delta=9.98 (s, 1H), 8.11 (d, 1H), 7.87 (d, 2H), 7.77 (m, 2H), 7.52 (d, 2H), 7.39 (m, 3H), 7.30 (m, 2H), 7.21 (d, 2H), 5.97 (m, 1H), 5.41 (s, 2H), 5.10 (m, 1H), 4.42 (m, 3H), 4.22 (m, 3H), 3.90 (m, 1H), 2.93 (m, 2H), 1.98 (m, 1H), 1.50 (m, 2H), 1.30 (m, 2H), 0.84 (m, 6H). |
76% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; | A solution of compound 28 (1 g, 2.01 mmol, leq) andp-aminobenzyl alcohol (273 mg, 2.21 mmol, 1.1 eq) in a mixture of DCM/MeOH (20 mL/10 mL) was treated with EEDQ (996 mg, 4.03 mmol, 2 eq). The mixture was stirred in the dark at room temperature overnight. The solvents were removed under vacuum and the resulting solid residue was triturated with 10 mL of ethyl ether. The solid was collected by filtration and washed with ethyl ether to yield the product (925 mg, 76% yield): 1H NMR (DMSO- |
65% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 16h;Darkness; | EEDQ (840 mg, 3.4 mmol) is added to a solution containing compound [12] (870 mg, 1 .7 mmol) and p-aminobenzyl alcohol (227 mg, 1 .8 mmol) in dichloro- methane/methanol 2:1 (15 mL). The reaction is left in the dark at room temperature for 16 hours. The solvents are removed, and the resulting solid residue filtrated using diethyl ether to give product [14] as a white solid, 660 mg (65% yield). MS: m/z 624 [M+Na]+.1H NMR (400 MHz, DMSO) delta 10.00 (bs, 1 H), 8.13 (m, 4H), 7.92 (d, J = 7.3 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.51 - 7.10 (m, 2H), 6.02 (s, 1 H), 5.43 (m, 4H), 5.13 (s, 1 H), 4.47 (s, 3H), 4.31 (m 4H), 3.13 - 2.74 (m, 2H), 2.03 (s, 1 H), 1 .83 - 1 .55 (m, 2H), 1 .43 (s, 2H), 0.90 (d, J = 6.7 Hz, 6H).13C NMR (101 MHz, DMSO) delta 171 .2, 170.4, 158.93, 156.15, 144.6, 143.8, 140.7, 137.5, 127.6, 127.2 (2C) 125.3, 120.1 (2C), 1 18.9, 65.7, 62.6, 60.1 , 53.0, 46.7, 31 .0, 30.5, 26.7, 19.6, 18.7. |
59% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 15h; | b) Fmoc-Val-Cit-PABA (32) A solution of Fmoc-Val-Cit-OH 31 (600 mg, 1.21 mmol), 4-aminobenzyl alcohol (298 mg, 2.42 mmol) and 2-Ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline (598 mg, 2.42 mmol) in CH2CI2/MeOH (12.6 ml_, 2:1 ) was stirred at rt for 15 h. Upon completion, the mixture was diluted with Et20 (30 ml_), sonicaated briefly, filtered and washed with Et20 to yield Fmoc- Val-Cit-PABC (428 mg, 0.710 mmol, 59%) as an off-white solid |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃;Darkness; | The reaction product of reaction step b (7.6 g, 15.3 mmol) and PABOH (3.76 g, 30.6 mmol) were dissolved in a mixture of 140 mL of CH2Cl2 and 70 mL of CH3OH.EEDQ (7.5 g, 30.6 mmol) was added in the dark.Stirring at room temperatureReaction, after the reaction is completed, spin the reaction solution,Wash with ether,Filter by suction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; for 16h; | As depicted in Scheme 15, Fmoc-Glutamine (Fmoc-Gln) (380 mg, 1.03 mmol, 1 eq) and p-aminobenzyl alcohol (133 mg, 1.08 mmol, 1.05 eq) were dissolved in THF (7 mL) and EEDQ (266.3 mg, 1.08, 1.05 eq) was added. After 16h, the mixture was evaporated to dryness at 30C, and the residue was triturated with ether (15 mL). The resulting off-white solid product was collected by filtration, washed with ether, and dried in vacuo (467 mg, 96%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-ureidopentanoic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -40℃; for 3h; Inert atmosphere; Stage #2: 4-aminobenzenemethanol With 4-methyl-morpholine In tetrahydrofuran at -40 - 23℃; for 21h; Inert atmosphere; | 1.1.1.4 Synthesis of Fmoc-Cit-PABOH (26) - (9H-fluoren-9-yl)methyl (hydroxymethyl)phenyl)amino)-1 -oxo-5-ureidopentan-2-yl)carbamate [00171 ] To a solution of 1 .0 g (2.516 mmol, 1 .0 eq) Fmoc-Cit-OH in 20 ml_ dry THF maintained under an argon atm. at -40°C were added 304 μΙ_ (2.768 mmol, 1 .1 eq) NMM and 358 μ (2.768 mmol, 1 .1 eq) /'so-butylchloroformate. The mixture was stirred for 3 h at -40°C before further 332 μΙ_ (3.019 mmol, 1 .2 eq) NMM and 372 mg (3.019 mmol, 1 .2 eq) para-aminobenzylalcohol were added. The mixture was stirred for an additional 1 h at -40°C and then allowed to warm to 23°C over a period of 20 h. The reaction mixture was concentrated under reduced pressure and the solid residue was purified by flash chromatography through silicagel (CH2Cl2:MeOH/95:5 - 9:1 - 8:2) yielding 1 .264 g (2.515 mmol, 100%) Fmoc-Cit-PABOH 26as an amorphous pale-yellow solid. (0274) [00172] Fmoc-Cit-PABOH (26):5 TCL (CH2CI2:MeOH/95:5) Rf: 0.10 [UV254, CAM], IR (ATR) [cm"1]: 3280, 3128, 3063, 2923, 2864, 1689, 1653, 1600, 1568, 1532, 1478, 1450, 1414, 1387, 1334, 1281 , 12551 , 1231 , 1 164, 1 153, 1 1 16, 1 103, 1085, 1044, 1033, 1016, 989, 938, 823, 797, 778, 756, 737, 701 , 674, 662, 640, 610. 1H-NMR (500 MHz, DMSO-c/e) δ [ppm]: 9.98 (s, 1 H), 7.89 (d, J = 7.5 Hz, 2H), 7.75 (t, J = 6.5 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.33 (q, J = 6.8 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.99 (t, J = 5.5 Hz, 1 H), 5.43 (s, 2H), 5.10 (t, J = 5.7 Hz, 1 H), 4.43 (d, J = 5.6 Hz, 2H), 4.30 - 4.25 (m, 2H), 4.25 - 4.20 (m, 1 H), 4.20 - 4.13 (m, 1 H), 3.1 1 - 2.99 (m, 1 H), 3.01 - 2.87 (m, 1 H), 1 .74 - 1 .63 (m, 2H), 1 .65 - 1 .54 (m, 2H), 1 .53 - 1 .44 (m, 2H), 1 .43 - 1 .34 (m, 2H). 13C- NMR (126 MHz, DMSO-c/6) δ [ppm]: 170.98, 158.90, 156.10, 143.88, 143.79, 140.70, 137.57, 137.39, 127.64, 127.64, 127.08, 127.06, 126.91 , 125.36, 120.10, 120.10, 1 18.85, 66.05, 65.67, 62.60, 55.03, 54.95, 46.66, 46.07, 29.34, 26.93. LRMS (0275) 5 The obtained analytic data were in completed accordance with prior published ones. (ESI-Quad) [m/z]: 503.3[M+H] HRMS (ESI-IT) [m/z]: 503.2294, calculated 503.2289 for C28H3iN4O5 [M+H]+, err [ppm] -1 .00. |
97% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane for 16h; | 1.1.1e To a solution of Fmoc-Cit-OH (1.0 g, 2.52 mmole) and 4-aminobenzylalcohol (341 mg, 2.77 mmole) in dichloromethane (10 mL) and methanol (5 mL) was added 2- ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline[EEDQ] (1.24g, 5.04 mmole) in one portion. The mixture was stirred in the dark for 16 hours. The solvents were removed on the rotovap, and the white solid was triturated with ether (100 mL). The resulting suspension was sonicated for 5 min and then left to stand for 30 min. The white solid was collected by filtration, washed with ether and dried in vacuo (1.23g, 97%). (at)H-NMR (DMSO) 8 1.32 to 1.52 (m, 2H), 1.52 to 1.74 (dm, 2H), 2.86 to 3.06 (dm, 2H), 4.1 (M, 1H), 4.42 (d , 2H), 5.07 (t, 1H), 5.40 (bs, 2H), 5.97 (t, 1H), 7.19 to 7.95 (m, 12H), 8.10 (d, 1H), 9.97 (s, 1H) ppm; LC-MS (ESI) 503.1 (M+H)+. |
90% | Stage #1: (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-ureidopentanoic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -40℃; for 2h; Stage #2: 4-aminobenzenemethanol With 4-methyl-morpholine In tetrahydrofuran at -40 - 20℃; for 3h; | 6 Example 6. Synthesis of citrulline derivative 32 Isobutylchloroformate (99 μ^, 0.76 mmol) and N-methylmorpholine (83 μ^, 0.76 mmol) were added to a solution of Fmoc-citrulline 31 (300 mg, 0.76 mmol) in THF at - 40 °C. The solution was stirred for 2h followed by the addition of p- aminobenzylalcohol (112 mg, 0,91 mmol) and N-methylmorpholine (100 μ^, 0.91 mmol). After lh stirring the solution was slowly warmed to rt and after 2h the reaction mixture was concentrated under reduced pressure. Purification via flash column chromatography (DCM:MeOH 99: 1-80:20) afforded citrulline derivative 32 (346 mg, 0.69 mmol, 90%). LRMS (ESI+) calcd for C28H30N4O5 ( +H+) 503.2, found 503.1. |
84% | With EEDQ In methanol; dichloromethane at 20℃; for 16h; Inert atmosphere; | a.i (i) To a solution of compound Ii (4.0 g. 10.0 mrnoi) in misture ofDCM and MeOH (100 mL / 50 inL) were added 4-amino-phenyi-rnethanoi (12) (1 €60 g, 13 mmoi, 1.3 eq) and EEDQ (12 g, 13mmdl, 1.3 eq. After the mixture was stirred at room temperature for 16 hours tiMer N2, LCMS showed compound H was consumed. The mixture was concentrated to give a brown sohd, and MTBE (200mL) was added and the mixture was stirred at 15°C for 2 hours. The solid was collected and washed with MTBE (50 mL x 2) to give 13 (4.2 g, 84%) as an orange solid. LCMS (ESI, S95 /1.5 mm’): RT = 0.807 mm, M+H = 503.0; ‘H NMR (400 MHz, DMSO-46) 9.98 (s,1H), 7.89 (d, J 7.2 Hz, 2 H), 7.73 (d, J 4.8 Hz, 2 H), 7.70 - 7.65 (in, I H), 7.56 (d, j::z 8.4 Hz,2. H), 7.41 (d, J= 7.2 Hz, 2 H), 7.33 7.32 (rn. 2 H), 7.24 d, ] = 8.4 Hz, 2 H), 5.99 (in, 1 H), 5.42(s, 2 H), 5.11 5.08 (t,J 5.6 Hz ,1 fl), 4.36 (d,J 5.6 Hz, 2 H), 4.27 (s, 2 H), 4.26- 4.18 (in, 2H), 3.33 -2.94 (m, 2 H’), 1.67- 1.59 (rn, 2 H), 1.47 1.40 (rn, 211). |
84% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16h; Inert atmosphere; | 13.2 Step 2 : Preparation of (S)- 1 -( 1 -(4-(hydroxymethyl)phenyl amino)- 1 -oxo-5 - ureidopentan-2-ylcarbamoyl)cyclobutanecarboxylic acid 10b To a solution of lOf (4 g, 10 mmol) in a mixture of DCM and MeOH (100 mL / 50 mL) were added (4-aminophenyl)methanol (1.6 g, 13 mmol, 1.3 eq) and 2-Ethoxy-l- ethoxycarbonyl-l ,2-dihydroquinoline, EEDQ, Sigma-Aldrich CAS Reg. No. 16357-59-8 (3.2 g, 13 mmol, 1.3 eq). After the mixture was stirred at r.t. for 16 h under N2, it was concentrated to give a brown solid. MTBE (200 mL) was added and it was stirred at 15°C for 2 h. The solid was collected by filtration, washed with MTBE (50 mL x 2) to give (S)-(9H- fluoren-9-yl)methyl ( 1 -((4-(hydroxymethyl)phenyl)amino)- 1 -oxo-5 -ureidopentan-2- yl)carbamate lOe as an orange solid (4.2 g, 84%). LCMS (ESI): m/z 503.0 [M+l]. |
84% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 0℃; for 16h; Inert atmosphere; | 9 To a solution of lOf (4 g, 10 mmol) in a mixture of DCM and MeOH (100 mL / 50 mL) were added (4-aminophenyl)methanol (1.6 g, 13 mmol, 1.3 eq) and 2-Ethoxy- 1 -ethoxycarbonyl1,2-dihydroquinoline, EEDQ, Sigma-Aldrich CAS Reg. No. 16357-59-8 (3.2 g, 13 mmol, 1.3 eq). After the mixture was stirred at r.t. for 16 h under N2, it was concentrated to give a brown solid. MTBE (200 mL) was added and it was stirred at 15°C for 2 h. The solid was collected by filtration, washed with MTBE (50 mL x 2) to give (S)-(9H-fluoren-9-yl)methyl (1-((4-(hydroxymethyl)phenyl)amino)- 1 -oxo-5 -ureidopentan-2-yl)carbamate 1 Oe as an orange solid (4.2 g, 84%). LCMS (ESI): mlz 503.0 [M+1]. |
84% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16h; Inert atmosphere; | B.1.A Step A: Synthesis of (S)-N-(5-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)pentyl)-N-(l- (4-(hydroxymethyl)phenylamino)- 1 -oxo-5 -ureidopentan-2-yl)cyclobutane- 1 , 1 -dicarboxamide 1 m [00342] To a solution of lg (4 g, 10 mmol) in a mixture of DCM and MeOH (100 mL / 50 mL) were added 4-amino-phenyl-methanol (1.6 g, 13 mmol, 1.3 eq) and EEDQ (3.2 g, 13 mmol, 1.3 eq). After the mixture was stirred at r.t. for 16 h under N2, it was concentrated to give a brown solid. MTBE (200 mL) was added and it was stirred at 15°C for 2 h. The solid was collected by filtration, washed with MTBE (50 mL χ 2) to give (S)-(9H-fluoren-9-yl)methyl (l-((4- (hydroxymethyl)phenyl)amino)-l-oxo-5-ureidopentan-2-yl)carbamate lh as an orange solid (4.2 g, 84%). LCMS (ESI): m/z 503.0 [M+l]. |
84% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16h; Inert atmosphere; | 1a.2 Step 2: Preparation of (S)-i -(1 -(4-(hydroxymethyl)phenylamino)- 1 -oxo-5- ureidopentan-2-ylcarbamoyl)cyclobutanecarboxylic acid 10b To a solution of lOf(4 g, 10 mmol) in a mixture of DCM and MeOH (100 mL/ 50 mL) were added (4-aminophenyl)methanol (1.6 g, 13 mmol, 1.3 eq) and 2-Ethoxy-1- ethoxycarbonyl- 1 ,2-dihydroquinoline, EEDQ, Sigma-Aldrich CAS Reg. No. 16357-59-8 (3.2 g, 13 mmol, 1.3 eq). After the mixture was stirred at r.t. for 16 h under N2, it was concentrated to give a brown solid. MTBE (200 mL) was added and it was stirred at 15°C for 2 h. The solid was collected by filtration, washed with MTBE (50 mL x 2) to give (S)-(9H- fluoren-9-yl)methyl (1 -((4-(hydroxymethyl)phenyl)amino)- 1 -oxo-5-ureidopentan-2- yl)carbamate lOe as an orange solid (4.2 g, 84%). LCMS (ESI): mlz 503.0 [M+l]. |
82% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane Darkness; Inert atmosphere; | |
80% | With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 20℃; for 30h; Darkness; Inert atmosphere; | Synthesis of Fmoc-Cit-PABOH: To a solution of Fmoc-Cit (1 .0 equiv) and PABOH (3.0 equiv) in DMF (0.2 M), DIPEA (1.0 equiv) was added and was stirred for 30 min at room temperature. Then HATU (1.1 equiv) was added to the reaction mixture and allowed to stir at room temperature for 30.0 h in dark. Solvent DMF was removed under reduced pressure. To the residue water and 10% iPrOH- EtOAc were added and was stirred to get clear phases. Organic phase was separated and aqueous phase was further extracted twice with 10% iPrOH-EtOAc. Collected organic phase was dried over sodium sulfate. Solvent was partially evaporated under reduced pressure and then slurry of crude product was made in celite for solid loading in column. Product was purified by silica gel column flash chromatography using 1 -12% MeOH-CH2Cl2. Compound Fmoc-Cit-PABOH was obtained as yellowish solid. Yield: 80%. |
71% | Stage #1: 4-aminobenzenemethanol; (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-ureidopentanoic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 48h; Darkness; | Synthesis of compound 17 A solution of compound 15 (2.907 g, 7.316 mmol, 1.0 equiv) and 4-aminobenzyl alcohol (2.703 g, 21.95 mmol, 3.0 equiv) in DMF (0.1M) was treated with DIPEA (1.30 mL, 7.32 mmol, 1.0 equiv) followed by stirring for 15 minutes at room temperature. HATU (3.059 g, 8.047 mmol, 1.1 equiv) was added to the reaction mixture and stirred at room temperature for 48 hours in the dark. DMF was removed under reduced pressure and the resulting residue was purified by flash column chromatography using 2-10% MeOH-CH2Cl2 as solvent. The product was isolated as white solid. Yield: 71%. |
67% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane for 15h; | 1c For Fmoc-Cit-PABA 2l, a solution of Fmoc-Cit-OH (345.7 mg, 0.87 mmol) and PABA (214 mg, 1.74 mmol) in DCM (10 ml) and MeOH (4 ml) was treated with EEDQ (430 mg,1.74 mmol) and stirred for 15 h. The solid product was triturated three times with ether,and the product was filtered and dried. Yield 288 mg (67%). MS: 502.3 [M+1] 485.5[M-H2O+1] 263 [M-Fmoc-H2O+1] 179.0 [M-306+1] 120.2 [M-365.3+1]. |
45% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran; dichloromethane at 20℃; for 16h; Inert atmosphere; | 9.a; 38.a (9H-fluoren-9-yl) met hyl-(,S')-( 1 -( (4-( hyd roxy methyl )phenyl)aniino )- 1-oxo- 5-reidopentan-2-yl)carbamate (77): (4-aminophenyl) methanol (75) (6 g, 4.87 mmol), Fmoc-Cit-OH (76) (23.24 g, 58.54 mmol), EEDQ (36.15 g, 146.34 mmol) were mixed in DCM-THF (1: 1) (600 ml) and stirred at ambient temperature under nitrogen for 16 h. The reaction mixture was reduced to dryness under vacuum and purified by column chromatography on a silica cartridge eluting with methanol I DCM gradient (5-10%). The solvent was evaporated under vacuum to obtain 11g (45%) of (9H-fluoren-9-yl)methyl (S)- (l-((4-(hydroxymethyl)phenyl)amino)-l-oxo-5-ureidopentan-2-yl)carbamatedesired product (77) as a white solid. 'H NMR (400 MHz, DMSO-rfe) 8 9.97 (s, 1H), 7.90 (d, 2H), 7.73-7.76 (q, 2H), 7.65-7.67 (d, 1H), 7.54-7.56 (d, 2H), 7.39-7.43 (t, 2H), 7.30-7.34 (m, 2H), 7.22-7.24 (d, 2H), 5.97-5.99 (t, 1H), 5.41 (s, 1H), 5.07-5.10 (t, 1H), 4.42-4.43 (d, 2H), 4.14-4.13 (m,4H), 4.07-4.11 (q, 1H), 3.16-3.17 (d,3H), 2.94-3.04 (m,2H), 1.59-1.68 (m, 2H), 1.38-1.47 (m,2H). LCMS: MH+ 503, retention time 2.91 min. |
45% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran; dichloromethane at 20℃; for 16h; Inert atmosphere; | 9.a; 38.a (9H-fluoren-9-yl) met hyl-(,S')-( 1 -( (4-( hyd roxy methyl )phenyl)aniino )- 1-oxo- 5-reidopentan-2-yl)carbamate (77): (4-aminophenyl) methanol (75) (6 g, 4.87 mmol), Fmoc-Cit-OH (76) (23.24 g, 58.54 mmol), EEDQ (36.15 g, 146.34 mmol) were mixed in DCM-THF (1: 1) (600 ml) and stirred at ambient temperature under nitrogen for 16 h. The reaction mixture was reduced to dryness under vacuum and purified by column chromatography on a silica cartridge eluting with methanol I DCM gradient (5-10%). The solvent was evaporated under vacuum to obtain 11g (45%) of (9H-fluoren-9-yl)methyl (S)- (l-((4-(hydroxymethyl)phenyl)amino)-l-oxo-5-ureidopentan-2-yl)carbamatedesired product (77) as a white solid. 'H NMR (400 MHz, DMSO-rfe) 8 9.97 (s, 1H), 7.90 (d, 2H), 7.73-7.76 (q, 2H), 7.65-7.67 (d, 1H), 7.54-7.56 (d, 2H), 7.39-7.43 (t, 2H), 7.30-7.34 (m, 2H), 7.22-7.24 (d, 2H), 5.97-5.99 (t, 1H), 5.41 (s, 1H), 5.07-5.10 (t, 1H), 4.42-4.43 (d, 2H), 4.14-4.13 (m,4H), 4.07-4.11 (q, 1H), 3.16-3.17 (d,3H), 2.94-3.04 (m,2H), 1.59-1.68 (m, 2H), 1.38-1.47 (m,2H). LCMS: MH+ 503, retention time 2.91 min. |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16h; Inert atmosphere; | To a solution of compound 7 (4.0 g, 10 mmol) in a mixture of DCM and MeOH (100 mL / 50 mL) were added 4-amino-phenyl-methanol (8) (1.6 g, 13 mmol, 1.3 eq) and EEDQ (3.2 g, 13 mmol, 1.3 eq). After the mixture was stirred at r.t. for 16 h under N2, it was concentrated to give a brown solid. MTBE (200 mL) was added and it was stirred at 15°C for 2 h. The solid was collected by filtration, washed with MTBE (50 mL x 2) to give the crude product 9 as an orange solid (4.2 g, 84%).LCMS (ESI): m/z 503.0 [M+1]. | |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16h; Inert atmosphere; | A To a solution of compound 7 (4 g, 10 mmol) in a mixture of DCM and MeOH (100 mL / 50 mL) were added 4-amino-phenyl-methanol (8) (1.6 g, 13 mmol, 1.3 eq) and EEDQ (3.2 g, 13 mmol, 1.3 eq). After the mixture was stirred at r.t. for 16 h under N2, it was concentrated to give a brown solid. MTBE (200 mL) was added and it was stirred at 15°C for 2 h. The solid was collected by filtration, washed with MTBE (50 mL x 2) to give the crude product 9 as an orange solid (4.2 g, 84%). LCMS (ESI): m/z 503.0 [M+l]. | |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16h; Darkness; | 1-2.2 Step 2: Fmoc-Cit-PAB-OH To a solution of crude Fmoc-cit (5.0 g, 11.4 mmol) and 4-aminobenzyl alcohol (1.8 g, 14.9 mmol) in 2:1 DCM/MeOH (150 mL) was added EEDQ (5.65 g, 22.84 mmol). The mixture was stirred in the dark at room temperature for 16 h and then concentrated. The residue was triturated with tert-butyl methyl ether (100 mL). The resulting suspension was sonicated and then left to stand for about 30 mm. The white solid was collected by filtration and washed repeatedly with tert-butyl methyl ether to give the crude title compound (5.5 g). | |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16h; Inert atmosphere; | 4.1 Step 1: (S)-N-(5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentyl)-N-(1-(4- (hydroxymethyl)phenylamino)-1-oxo-5-ureidopentan-2-yl)cyclobutane-1,1-dicarboxamide To a solution of compound 7 (4 g, 10 mmol) in a mixture of DCM and MeOH (100 mL / 50 mL) was added 4-amino-phenyl-methanol (8) (1.6 g, 13 mmol, 1.3 eq) and EEDQ (3.2 g, 13 mmol, 1.3 eq). After the mixture was stirred at r.t. for 16 h under N2, it was concentrated to give a brown solid. MTBE (200 mL) was added and it was stirred at 15oC for 2 h. The solid was collected by filtration, washed with MTBE (50 mL × 2) to give the crude product 9 as an orange solid (4.2 g, 84%). LCMS (ESI): m/z 503.0 [M+1]. | |
With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In dichloromethane at 20℃; for 16h; | 2.2.96.2.96.1 2.96.1. (S)-(9H-fluoren-9-yl)methyl (1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)carbamate [0001026] S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-ureidopentanoic acid (40 g) was dissolved in dichloromethane (1.3L). (4-Aminophenyl)methanol (13.01 g), 2-(3H-[l,2,3]triazolo[4,5- b]pyridin-3-yl)-l, l,3,3-tetramethylisouronium hexafluorophosphate(V) (42.1 g) and N,N- diisopropylethylamine (0.035 L) were added to the solution, and the resulting mixture was stirred at room temperature for 16 hours. The product was collected by filtration and rinsed with dicholoromethane. The combined solids were dried under vacuum to yield the title compound, which was used in the next step without further purification. MS (ESI) m/e 503.3 (M+H)+. | |
With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In dichloromethane at 20℃; for 16h; | 2.2.96.2.96.1 2.96.1 (S)-(9H-fluoren-9-yl)methyl (1-((4- (hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2- yl)carbamate (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-ureidopentanoic acid (40 g) was dissolved in dichloromethane (1.3L). (4-Aminophenyl)methanol (13.01 g), 2-(3H-[1,2,3]triazolo[4,5- b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (42.1 g) and N,N- diisopropylethylamine (0.035 L) were added to the solution, and the resulting mixture was stirred at room temperature for 16 hours. The product was collected by filtration and rinsed with dichloromethane. The combined solids were dried under vacuum to yield the title compound, which was used in the next step without further purification. MS (ESI) m/e 503.3 (M+H)+. | |
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 16h; | 2.96.1 2.96.1 (S)-(9H-fluoren-9-yl)methyl (1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)carbamate (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-ureidopentanoic acid (40 g) was dissolved in dichloromethane (1.3L). (4-Aminophenyl)methanol (13.01 g), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (42.1 g) and N,N-diisopropylethylamine (0.035 L) were added to the solution, and the resulting mixture was stirred at room temperature for 16 hours. The product was collected by filtration and rinsed with dichloromethane. The combined solids were dried under vacuum to yield the title compound, which was used in the next step without further purification. MS (ESI) m/e 503.3 (M+H)+. | |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 30℃; Inert atmosphere; | ||
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 16h; | 2.1.1 2.1.1. (S)-(9H-fluoren-9-yl)methyl (1-((4-(hydroxymethyl) phenyl)amino)- 1-oxo-5-ureidopentan-2-yl)carbamate (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-ureidopentanoic acid (40 g) was dissolved in dichloromethane (1. 3L). (4-Aminophenyl)methanol (13.01 g), 2-(3H-[ 1 ,2,3jtriazolo[4,5-b]pyridin-3 - yl)- 1,1,3,3 -tetramethylisouronium hexafluorophosphate(V) (42.1 g) and N,N-diisopropylethylamine(0.035 L) were added to the solution, and the resulting mixture was stirred at room temperature for 16 hours. The product was collected by filtration and rinsed with dichloromethane. The combined solids were dried under vacuum to yield the title compound, which was used in the next step without further purification. MS (ESI) mle 503.3 (M+H)t | |
With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In dichloromethane at 20℃; for 16h; | 2.1.1 2.1.1. (S)-(9H-fluoren-9-yl)methyl (1-((4-(hydroxymethyl) phenyl)amino)-1-oxo-5-ureidopentan-2-yl)carbamate (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-ureidopentanoic acid (40 g) was dissolved in dichloromethane (1.3 L). (4-Aminophenyl)methanol (13.01 g), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (42.1 g) and N,N-diisopropylethylamine (0.035 L) were added to the solution, and the resulting mixture was stirred at room temperature for 16 hours. The product was collected by filtration and rinsed with dichloromethane. The combined solids were dried under vacuum to yield the title compound, which was used in the next step without further purification. MS (ESI) m/e 503.3 (M+H)+. | |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane | ||
6.0 g | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane at 20 - 45℃; for 6h; | 8.1 Step 1: Synthesis of methyl (S)-(1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)-(9H-fluorenyl)carbamate (Compound 19-2). At room temperature, Fmoc-L-citrulline (5.0 g, 12.58 mmol), p-aminobenzyl alcohol (6.20 g, 50.32 mmol) and 2-ethoxy-1-ethoxycarboxyl-1,2-dihydroquinoline (6.22 g, 25.16 mmol) were dissolved in dichloromethane (100 mL), and heated to 45°C. and reacted for 6 h. The reaction solution was concentrated under reduced pressure, and beaten with anhydrous diethyl ether (100 mL) to obtain the title compound (6.0 g). [0322] ESI-MS (m/z): 503.3 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3.0h; | 215; 4-Oxo-N-phenyl-lH-quinoline-3-carboxamide;To a solution of <strong>[34785-11-0]4-hydroxy-quinoline-3-carboxylic acid</strong> (A-l) (19 mg, 0.1 mmol), HATU (38mg, O.lmmol) and DIEA (34.9 |J,L, 0.2mmol) in DMF (1 mL) was added aniline (18.2 uL, 0.2mmol) and the reaction mixture was stirred at room temperature for 3 h. The resulting solutionwas filtered and purified by HPLC (10-99 % CH3CN / H2O) to yield 4-oxo-N-phenyl-lH-quinoline-3-carboxamide (215) (12 mg, 45 %). .H NMR (400 MHz, DMSO-J6) 8 12.97 (s, 1H),12.50 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J = 8.1,1.1 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.75 (m, 3H),7.55 (t, J = 8.1 Hz, 1H), 7.37 (t, J - 7.9 Hz, 2H), 7.10 (t, J = 6.8 Hz, 1H); HPLC ret. time 3.02min, 10-99 % CH3CN, 5 min run; ESI-MS 265.1 m/z (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In tetrahydrofuran; thionyl chloride; | Preparation of 3,5-dichloro-N-(4-hydroxymethyl-phenyl)-isonicotinamide: A suspension of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (128 mg, 0.667 mmol) in thionyl chloride (2 mL) was heated at reflux for 2 h, then concentrated. To the residue was added 4-aminobenzyl alcohol (123 mg, 0.999 mmol) and THF (2.2 mL), and the mixture was stirred at room temperature for 19 h. The mixture was filtered, and the filtrate was concentrated to give a yellow foam (125 mg, 63%). 1H NMR (CD3OD) delta 4.60 (s, 2H), 7.38 (d, 2H, J=8.7 Hz), 7.63 (d, 2H, J=8.4 Hz), 8.66 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 0.55 g (5 mmol) of p-aminobenzylalcohol and 2.0 ml of triethylamine in 30 ml of chloroform, a solution of 2 g (5.5 mmol) of N-t-BOC-L-phenylalanine N-hydroxysuccinimidyl ester (Sigma Chemical Company, St. Louis, MO; product number B1880) in 20 ml of chloroform is added dropwise at 0 DEG C. The mixture is allowed to warm up to room temperature, and then is poured into 50 ml of 5% aqueous HCI. After stirring the aqueous mixture for 4 hours at room temperature, the organic layer is separated and discarded, and the aqueous layer is extracted twice with 30 ml of chloroform. The aqueous layer is evaporated to dryness under vacuum to leave the product L-phenylalanine amide of p-aminobenzylalcohol hydrochloride salt as a residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 0.55 g (5 mmol) of p-aminobenzylalcohol and 2.0 ml of triethylamine in 30 ml of chloroform, a solution of 2.4 g (5.5 mmol) of N,N-alpha,epsilon-di-t-BOC-L-lysine N-hydroxysuccinimidyl ester (Sigma Chemical Company, St. Louis, MO; product number B7019) in 20 ml of chloroform is added dropwise at 0 DEG C. The mixture is allowed to warm up to room temperature, and then is poured into 50 ml of 5% aqueous HCI. After stirring the aqueous mixture for 4 hours at room temperature, the organic layer is separated and discarded, and the aqueous layer is extracted twice with 30 ml of chloroform. The aqueous layer is evaporated to dryness under vacuum to leave the product L-lysine amide of p-aminobenzylalcohol hydrochloride salt as a residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With acetic acid; In 1,2-dichloro-ethane; at 20℃; for 0.5h; | A mixture of <strong>[75390-44-2]4-phenyl-1,3-thiazole-2-carbaldehyde</strong> (1.10 g, 5.81 mmol), (4-aminophenyl)methanol (615 mg, 5.0 mmol), acetic acid (0.4 mL) and 1,2-dichloroethane (10 mL) was stirred at room temperature for 30 min. The reaction mixture was diluted with hexane. The precipitated solid was collected by filtration, washed with hexane, and dried to give the title compound (1.30 g, yield 88%) as yellow crystals. 1H NMR (DMSO-d6) delta: 4.54(2H, d, J=5.7Hz), 5.25 (1H, t, J=5.7Hz), 7.36-7.55(7H, m), 7.99-8.08 (2H, m), 8.39 (1H, s), 8.92 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2.5h; | 3-1.1 (1) Diisopropylethylamine (673 μL) was added to a DMF solution (2.0 mL) of 5-hydroxyindole-2-carboxylic acid (516 mg), 4-amino-benzyl alcohol (262 mg) and HATU (734 mg), and stirred at room temperature for 2.5 hours. The reaction liquid was diluted with ethyl acetate, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water. The organic layer was dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was diluted with diethyl ether and the resulting crystal was taken out through filtration to obtain 5-(benzyloxy)-N-[4-(hydroxymethyl)phenyl]-1H-indole-2-carboxamide (541 mg) as a brown solid. ESI-MS Found: m/z 373[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; di-tert-butyl dicarbonate; | Example 9 N-[(1S,2R)-2-([(S)-cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-6-[(methylsulfonyl)amino]-1H-indole-2-carboxamide To 4.97 g (40.35 mmol) of 4-aminobenzylalcohol dissolved in 30 mL of was added 9.69 g (44.39 mmol) of di-tert-butyl dicarbonate. The mixture was stirred at room temperature overnight, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated to provide 8.4 g t-butyloxycarbonyl-protected 4-aminobenzyl alcohol, as a colorless solid. To 4.79 g (21.65 mmol) of the above compound dissolved in 50 mL dichloromethane was added 9.19 g (21.65 mmol) Dess-Martin periodinane. The mixture was stirred for 2 h, partitioned between dichloromethane and water, dried over magnesium sulfate and concentrated. The product was purified using column chromatography, eluding with 25% ethyl acetate/hexane, to provide 3.0 g of tert-butyl 4-formylphenylcarbamate as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In ethanol; toluene at 20℃; for 4h; | 13.A A solution of Boc-Leu-OH (2.02 g, 8.10 mmol), 4-aminobenzyl alcohol (1.00 g, 8.10 mmol), and EEDQ (2.21 g, 8.90 mmol) in 1:1 toluene: ethanol (20 rnL) was stirred at room temperature under nitrogen for 4 hours. The solution was concentrated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel, eluting consecutively with 1:4 ethyl acetate:hexanes, 1:2 ethyl acetate:hexanes, and 1:1 ethyl acetate:hexanes to give the title compound as a colorless solid (2.62 g, 96%). 1H NMR (CDCl3): δ 8.46 (s, IH), 7.49 (d, J = 8.3 Hz5 2H), 7.28 (d, J = 8.3 Hz, 2H), 4.98 (s, IH), 4.64 (s, 2H), 4.27 (s, IH), 1.83-1.73 (m, 2H), 1.70 (s, IH), 1.62-1.55 (m, IH), 1.47 (s, 9H), 1.030.93 (m, 6H). MS (ESI): 237.3 (100, M-Boc+H). HRMS: Calcd for C18H28N2O4 (M+H): 337.2122; Found: 337.2118. |
96% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In ethanol; toluene at 20℃; for 4h; | 24.A A solution OF BOC-LEU-OH (2.02 g, 8.1 mmol), PABA (1.00 g, 8.1 mmol), and EEDQ (2.21 g, 8.9 mmol) in 1: 1 toluene: ethanol (20 mL) was stirred at room temperature under nitrogen for 4 hours. The solution was concentrated under reduced pressure and the resulting residue was chromatographed on silica gel, eluting consecutively with 1: 4 ethyl acetate: hexanes, 1: 2 ethyl acetate: hexanes, and 1: 1 ethyl acetate: hexanes to give the title compound as a colorless solid (2.62 g, 96%). |
85% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane at 20℃; for 1h; Inert atmosphere; | 1 Synthesis of tert-butyl(S)-(1-((4-(hydroxymethyl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (Compound TS30) Under a nitrogen atmosphere, DCM (2.00 mL) was added to a mixture of (tert-butoxycarbonyl)-L-leucine (231 mg, 1.00 mmol) and 4-aminophenyl methanol (123 mg, 1.00 mmol) and stirred. Then, ethyl 2-ethoxyquinolin-1(2H)-carboxylate (272 mg, 1.10 mmol) was added at room temperature, and this was stirred for another hour. The reaction solution was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile) to give tert-butyl (S)-(1-((4-(hydroxymethyl)phenyl) amino)-4-methyl-1-oxopentan-2-yl)carbamate (Compound TS30) (285.0 mg, 85.0%). LCMS (ESI) m/z=335 (M+H)- Retention time: 0.66 minutes (analysis condition SQDFA05) |
68% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In dichloromethane; for 10h; | For Fmoc-Leu-PABA 2j, a solution of Fmoc-Leu-OH (353 mg, 1 mmol), EEDQ (495 mg, 2 mmol) and PABA (222 mg, 1.8 mmol) in DCM (10 ml) was stirred for 10 h. All volatiles were removed on a rotovap, the residue was dissolved in Et2O (40 ml), chilled on dry ice for 2h and the solid was separated by centrifugation. The obtained crude material was purified on a column, eluent gradient of MeOH (1-2%) in CHCl3. Yield 444 mg (97%). MS: 459.4 [M+1]+. |
93% | Fmoc-Leu-OH (0.18 g, 0.50mmol) was dissolved in 5mLof tetrahydrofuran under argon flow and the solution wascooled to -10 C in a 1:3 NaCl: ice bath. Nmethylmorpholine(NMM, 0.11mL, 1.0mmol) and isobutylchloroformate (0.065mL, 0.50mmol) were added dropwisewith stirring. After 15 min, p-aminobenzyl alcohol (0.10 g,Development of an effective fluorescence probe for discovery of aminopeptidase inhibitors to suppress. . .0.50mmol) was added and the reaction was allowed to proceedwith stirring under argon flow at -10 C for 2 h. Thereaction was then allowed to proceed overnight with stirringat room temperature under an argon atmosphere for 20 h intotal. The crude reaction mixture was concentrated in vacuoand diluted with 8mL of ethyl acetate (EtOAc). This organicsolution was extracted with 1M Na2HPO4, brine, 5%NaHCO3, and brine, 8mL of each, subsequently. The combinedaqueous solution was extracted with 10mL of EtOAc.The combined organic mixture was then evaporated and runon a flash column in DCM/MOH=100:1. The purifiedproduct was evaporated to dryness to afford white solid 4(213 mg, 0.465 mmol, 93% yield). 1H NMR (400MHz,CDCl3) delta 8.14-7.93 (br, 1 H), 7.76 (d, J=7.5 Hz, 2 H), 7.56(d, J=7.2 Hz, 2 H), 7.47 (d, J=8.0 Hz, 2 H), 7.39 (t, J=7.4Hz, 2 H), 7.32-7.26 (m, 4 H), 5,25-5.11 (m, 1 H), 4.64 (s,2H), 4.51-4.40 (m, 2H), 4.34-4.24 (m, 1H), 4.21 (t, J=6.5Hz, 1 H), 1.84-1.74 (m, 1H), 1.73-1.63 (m, 2H), 1.0 -0.89(m, 6 H). 13C NMR (101 MHz, CDCl3) delta 170.6, 143.6, 141.3,136.9, 127.7, 127.1, 124.9, 120.0, 67.2, 64.8, 54.2, 47.0, 40.9,24.7, 22.9. ESI+-MS: [M+H]+ calculated for C28H31N2O4+:459.2278; found: 459.2281 | |
92% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In dichloromethane; at 20℃; | p-Aminobenzyl alcohol (PAB-OH) (310 mg, 2.59 mmol) was added to a solution of Fmoc-Leu-OH (830 mg, 2.35 mmol) and /V-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline (EEDQ) (630 mg, 2.59 mmol) in anhydrous dichloromethane (DCM) (50 ml_) and the reaction solution was stirred at room temperature overnight. The solvent was then evaporated under reduced pressure and the residue was purified by column chromatography eluting with DCM:MeOH 98:2 to afford 1 (1.00 g, 92%) as a colourless powder |
92% | Synthesis of Fmoc-Leu-PABOH (1) Fmoc-Leu-OH (2.50 g, 7.07 mmol) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (1.90 g, 7.78 mmol) were dissolved in anhydrous dichloromethane (DCM) (150 mL). After stirring at room temperature for 5 minutes, 4-aminobenzylalcohol (PABOH) (0.95 g, 7.78 mmol) was added and stirring was continued for 24 hours. DCM was then removed under reduced pressure and the product was purified on a silica gel column using chloroform/methanol (50 : 1) to afford 1 (3.00 g, 92%) as a white powder. APCI-MS (5 uA, MeCN): m/z (%) = 459.0 (100) [M + H]+; HPLC (220 nm): > 95%. | |
78% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In ethanol; toluene; at 20℃; for 92h; | A solution of Fmoc-Leu-OH (2.0 g, 5.7 mmol), PABA (0.7 g, 5.7 MMOL), and EEDQ (1.4 g, 6.3 mmol) in 1: 1 toluene: ethanol (30 ML) was stirred at room temperature under nitrogen for 3 days. Additional PABA (0.14 g, 1.1 mmol) was added and the reaction was stirred for another 18 hours. Additional EEDQ (0.4 g, 1.9 mmol) was added and the reaction was stirred for another 2 hours, and concentrated. The resulting residue was dissolved in dichloromethane (20 ML), washed consecutively with 1N HC1 (3 x 20 mL), saturated NAHC03 (3 x 20 mL), and brine (20 mL), dried (MGS04), and concentrated. The resulting solid was purified by flash chromatography on silica gel, eluting with 50: 1 dichloromethane : methanol to give the title compound as a colorless solid (2.03 g, 78%). |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In dichloromethane; at 20℃; | To a solution of N-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline(EEDQ) (3.15 g, 2.59 mmol) and Fmoc-L-Leu (1, 4.15 g,2.35 mmol) in anhydrous DCM (250 mL) was added 4-aminobenzylalcohol (PAB-OH) (1.55 g, 2.59 mmol). The mixture was continuouslystirred at room temperature for 24 h. The solvent was thenevaporated under reduced pressure and the resulting residue waspurified by silica gel chromatography (DCM/MeOH 50 : 1 to 10 :1) to afford 2 (1.00 g, 73%) as a colorless powder. ESI-MS: m/z 459.2[MH], 481.2 [MNa], HPLC analysis (l 220 nm) > 95% of peakarea. |
72% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 48h; | Reference literature (Elsadek B, Graeser R, Esser N, et al. Development of a novel prodrug of paclitaxel that is cleaved by prostate - specific antigen: An in vitro and in vivo evaluation study [J]. European Journal of Cancer, 2010, 46 (18): 3434 - 3444) employed in the two-step reaction method after the completion of the bridging group Leu - PABOH synthesis and modify. Namely: in 25 ml, adding 1 mmol of Fmoc - L - Leu (1), 2 mmol of p-aminophenylmethanol (PABOH) and 2 mmol condensing agent 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), adding 14 ml of methanol and 7 ml of methylene chloride as the reaction solvent, under the condition of room temperature light [...] 48 h, TLC (DCM:MeOH=55:1) monitoring, after the reaction, concentrated under reduced pressure to remove the organic solvent, by dichloromethane: methanol (100:1 - 70:1) system purification, gain the light yellow intermediate Fmoc - Leu - PABOH (2), yield 73%; [...], adding 1 mmol of Fmoc - Leu - PABOH intermediate (2), 2 mmol of b (P) carbonate, N2Protection, by adding 10 ml anhydrous N, N - dimethyl formamide (DMF) after dissolving the sample, under the condition of zero degrees Celsius, slowly adding 1.5 mmol of diisopropylethylamine (DIPEA), 5 min down to the room temperature, TLC (PE:ACE=3:1) monitoring the reaction, about 8 - 12 H-reaction is complete; after completion of the reaction, adding a large amount of saturated aqueous solution of salt (NaCl) and the termination of the reaction, ethyl acetate (EA) layered extraction three times, the combined organic phase, when the pressure of the relatively pure white solid precipitated, filtering, the remaining organic phase combined, by silica gel column purification (PE:ACE=10:1 - 7:1) and re-crystallization, to obtain white solid Fmoc - Leu - PABC - PNP (3), the overall yield is 82%. |
69% | portion of HBTU (1.6 g, 4.3 mmol) was added to a solution of Fmoc-Leu(OH) (1 g, 2.8 mmol) dissolved in 5 mL of 4% NMM in DMF and was left to stir under N2 for10 min. A portion of p-aminobenzyl alcohol (357 mg, 2.89 mmol) was then added to the reactionmixture under N2. After stirring for 5 h the reaction mixture was added to 50 mL of DCM andwashed 3 times with 50 mL of 10% LiCl in water. The organic layer was dried over sodiumsulphate and evaporated to dryness under vacuum. Flash silica-gel chromatography (3.5 %MeOH in CH2Cl2) afforded 1 as a white solid (954 mg, 69%). | |
63% | With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h; | PSA targeted prodrug was synthesized via scheme 1. The PSA targeting peptide was synthesized by solid phase peptide synthesis. Commercially available Fmoc-protected leucine was coupled with /j>-aminobenzyl alcohol (PAB) by following standard amide coupling protocol. Following bromination, intermediate 2 was reacted with sodium diethyl dithiocarbamate to give 3. Fmoc deprotection of 3 affords Leu-PAB-DTC 4. Compound 4 was coupled to the PSA targeting peptide synthesized via solid phase peptide synthesis to give PSA-DTC, PSA-targeting prodrug (Scheme 1). A) p-Aminobenzyl alcohol, HBTU, 4% NMM in DMF, 3h, rt, 63%; B) PBr3, Dry THF, 3 h, 0 C, 78%; C)(i) Sodium diethyldithiocarbamate, Dry THF, 12 h, rt (ii) 1% DBU in THF, 5 min, rt, 85%; D) FmocRSSYYS, HOBt, EDC, DIPEA, DMF, 12 h, rt; E) 20% piperidine in DMF, 3 h, rt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 1,4-dioxane; water; at 20℃; | Example 278 : Synthesis of (1E,6E)-1-[4-(tert-butoxycarbonylamino)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (CU405); (1) Synthesis of 4-(tert-butoxycarbonylamino)benzaldehyde; To a solution of 4-aminobenzyl alcohol (2.00 g, 16.2 mmol) in 10 mL of dioxane was added a solution of sodium hydroxide (0.65 g, 16 mmol) in 40 mL of water at room temperature. After addition of di-tert-butyl carbonate (4.95 g, 22.7 mmol), the reaction mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether, and the solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 4-(tert-butoxycarbonylamino)benzyl alcohol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.85% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; | I-11.1 Step 1. Synthesis of tert-butyl (2-((4-(hydroxymethyl)phenyl)amino)-2- oxoethyl)carbamate I-llb Into a 100-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of argon, were placed p-aminobenzylalcohol (2.87 g, 23.304 mmol, 1.00 eq), THF (60 mL), DCC (7.21 g, 34.956 mmol, 1.5 equiv) and [(tert-butoxycarbonyl)amino]acetic acid (4.90 g, 27.965 mmol, 1.2 eq). The resulting solution was stirred for 2 hours at room temperature. After filtration, the resulting mixture was concentrated to give a residue, which was purified by Flash-Prep-HPLC eluting with ACN in 5-95% water to provide 6 g (91.85%) of tert-butyl N-([[4-(hydroxymethyl)phenyl]carbamoyl]methyl)carbamate. LC-MS (ES, m/z): 281.20 [M+H]+ |
43% | Stage #1: BOC-glycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.5h; Stage #2: 4-aminobenzenemethanol With triethylamine In dichloromethane at 0℃; | 4.1.1. Methyl ((2S,3R)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-phenylbut-anoyl)-L-leuc-inate (5) General procedure: To a solution of compound 4 (1.0 g, 3.39 mmol) in dry DCM, EDCI(0.78 g, 4.06 mmol) and HOBt (0.55 g, 4.06 mmol) were added at 0 C.After 30 min, methyl L-leucinate hydrochloride (737.5 mg, 4.06 mmol)and TEA (0.75 g, 7.5 mmol) were added. The reaction was allowed to stirovernight, then was washed with 1 M HCl aqueous solution, and brinefor 3 times, and dried over anhydrous MgSO4. Volatiles were removedunder vacuum to get the crude residue which was purified via flashchromatography to afford the compound 5, a white solid powder (0.89g, yield: 62%). 1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 8.6 Hz, 1H),7.33-7.05 (m, 5H), 6.23 (d, J = 9.4 Hz, 1H), 6.02 (d, J = 6.5 Hz, 1H),4.34-4.15 (m, 1H), 4.00-3.85 (m, 1H), 3.84-3.77 (m, 1H), 3.60 (s, 3H),2.82-2.71 (m, 1H), 2.66-2.57 (m, 1H), 1.89-1.72 (m, 1H), 1.42-1.31 (s,9H), 0.86-0.68 (m, 6H). |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; | 268.1 Example 268 : Synthesis of (1E,6E)-1-(4-hydroxyphenyl)-7-{4-[2-(tert-butoxycarbonylamino)acetylamino]phenyl}hepta-1,6-diene-3,5-d ione (CU395); (1) Synthesis of 4-[2-(tert-butoxycarbonylamino)acetylamino]benzaldehyde; To a solution of 4-aminobenzylalcohol (300 mg, 2.43 mmol), N-Boc-glycine (426 mg, 2.43 mmol), and 1-hydroxybenzotriazole (344 mg, 2.55 mmol) in 4.8 mL of dry N,N-dimethylformamide was added N,N-diisopropylethylamine (0.42 mL, 2.9 mmol). After addition of 1-ethyl-3-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (489 mg, 2.55 mmol) at 0°C, the solution was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 4-[2-(tert-butoxycarbonylamino)acetylamino]benzylalcohol. |
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate | 12 Example 12: (E)-4-(2-Aminoacetamido)benzyl 2-methoxy-4-((8-methylnon-6- enamido)methyl)phenyl carbonate (24) The title compound (24) is prepared as outlined above. (4-Aminophenyl)methanol is coupled to N-Boc glycine to give compound 23. Compound 23 is then reacted with compound 7 from Example 4. Following deprotection, the title compound (24) is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a solution of <strong>[99-58-1]3-bromo-4-methoxy-benzoic acid</strong> (1.15 g, 5.0 mmol) in methylene chloride (10.0 mL) was added oxalyl chloride solution in methylene chloride (2 M, 3 mL, 6.0 mmol). Four drops of DMF was added with stirring at ambient temperature. Volatile materials were completely removed by evaporation under vacuum after it was stirred at ambient temperature for 1.5 h to give a residue. To the residual was added DMAP (20 mg), 4-aminobenzyl alcohol (0.615 g, 5.0 mmol) and THF (20 mL). Then, Et3N (1 ml) was added. The mixture was stirred at room temperature for 24 hrs. Then THF was removed under vacuum and water (20 mL) was added. The solid formed was filtered and washed with water (2 x 5 ml), ether (3 x 15 mL). An off-white solid (1.34 g, 80 %) was obtained. MS m/z = 337 (M+2). MS m/z = 337 (M+2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With acetic acid In benzene at 80℃; for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 18 h / 60 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / dichloromethane; toluene / 3 h / -78 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere 3.2: 20 h / 60 °C / Inert atmosphere 4.1: osmium(VIII) oxide; water; 4-methylmorpholine N-oxide / acetone / 44 h / 20 °C 5.1: sodium periodate / methanol; water / 0.5 h 6.1: tris(2-carboxyethyl)phosphine / water; acetonitrile / pH 7.4 / aq. phosphate buffer; Inert atmosphere 7.1: water; acetonitrile / pH 7.4 / aq. phosphate buffer; Inert atmosphere | ||
Multi-step reaction with 8 steps 1: tetrahydrofuran / 18 h / 60 °C / Inert atmosphere 2: diisobutylaluminium hydride / dichloromethane; toluene / 3 h / -78 °C / Inert atmosphere 3: triethylamine / dichloromethane / 23 h / 0 - 20 °C / Inert atmosphere 4: osmium(VIII) oxide; water; 4-methylmorpholine N-oxide / acetone / 20 °C / Darkness 5: sodium periodate; silica gel / tetrahydrofuran; diethyl ether; water / 0.5 h / 20 °C 6: triethylamine / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 7: tris(2-carboxyethyl)phosphine / water; acetonitrile / pH 7.4 / aq. phosphate buffer; Inert atmosphere 8: water; acetonitrile / pH 7.4 / aq. phosphate buffer; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In tetrahydrofuran; methanol; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | Boc-Val-Cit-PABOH (82) A solution of Boc-Val-OSu (10.0 g, 31.8 mmol, 1 eq.) in THF (50 mL) was added to a solution of H-Cit-OH (5.85 g, 33.4 mmol, 1.05 eq.) and NaHCO3 (2.94 g, 34.9 mmoL, 1.1 eq.) in THF (50 mL) and H2O (100 mL). The mixture was stirred at room temperature for 72 hours and the THF was evaporated under reduced pressure. The pH was adjusted to 3 with citric acid to precipitate a white gum. This was extracted with 10% IPA/ethylacetate (8*150 mL), the combined extracts were washed with brine (300 mL) and dried (MgSO4). Evaporation under reduced pressure gave a white foam which was dried under reduced pressure for 18 hours. The foam was suspended in ether with sonication followed by filtration to give the product as a fine white powder (10.6 g, 89%). A portion of this material (7.2 g, 19.2 mmol, 1 eq), p-aminobenzyl alcohol (2.6 g, 21.15 mmol, 1.1 eq.) and EEDQ (9.5 g, 38.5 mmol, 2.0 eq.) in DCM/MeOH (100 mL/50 mL) were stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residual gum was triturated with ether with sonication, the resulting product was collected by filtration and dried under reduced pressure to give the product 82 as a white solid (6.6 g, 71%). Analytical Data: RT 2.42 min; MS (ES+) m/z (relative intensity) 479.8 ([M+1]+., 60), MS (ES-) m/z (relative intensity) 477.6 ([M-H])-., 90). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 1H-Indole-3-carboxylic acid, 1-(phenylmethyl)-(CAS 27018-76-4) (1.0 g, 3.7 mmol) in DCM (10 mL) was added oxalyl chloride (0.950 mgs, 7.5 mmol) followed by the addition of DMF (3 drops) at room temperature. The solvent was removed under reduced pressure and gave the crude product. To the crude material in DCM (10 mL) was added (4-aminophenyl)methanol, (0.478 mgs, 3.8 mmol), followed by triethylamine (0.98 ml, 7.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted in DCM. The organic layer was separated and dried over magnesium sulphate and the solution was filtered. The filtrate was evaporated under reduced pressure to give the crude product, which was purified on a column (MPLC) using DCM:MeOH and gave Intermediate 7 (550 mgs).1H NMR (300 MHz, CD3OD) delta: 8.48 (s, 1H), 8.51-8.62 (m, 2H), 7.24-7.33 (m, 7H), 7.82 (d, J=8.1 Hz, 2H), 8.95 (d, J=8.1 Hz, 2H), 5.41 (s, 2H), 4.61 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With ammonium iodide; hydrazine; at 50℃; for 18h; | Purification by column chromatography (ethyl acetate/hexane = 2/1) provided a white solid product. Yield 116 mg (94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
-(4-(Hydroxymethyl)phenyl)-3-(trifluoromethoxy)benzamide (5.8.2)To a stirring solution of <strong>[1014-81-9]3-(trifluoromethoxy)benzoic acid</strong> (1 .00 g, 4.87 mmol) in DMF (10 ml) was added HATU (1 .54 g, 4.06 mmol) and DIPEA (1 .42 mL, 8.12 mmol). The reaction was allowed to stir for 10 min and the 4-amino benzyl alcohol (0.50 g, 4.06 mmol) was added. The solution was stirred overnight at room temperature. An LC-MS was obtained which indicated the presence of the product. Water was added and the precipitate was filtered to yield a brownish solid. This was purified by column chromatography to yield the product as an off-white solid. The product was confirmed by LC-MS. See Table 19 for analytical data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 2: piperidine / N,N-dimethyl-formamide | ||
Multi-step reaction with 3 steps 1.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane / 20 °C / Inert atmosphere 1.2: 24 h / 20 °C / Inert atmosphere 2.1: piperidine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3.1: 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 0 °C / Inert atmosphere 3.2: 4 h / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With benzotriazol-1-ol; diisopropyl-carbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 23℃; for 2h; | To a solution of Compound 10 (1 .6 g, 3.42 mmol) and 4-aminobenzyl alcohol (PABOH) (0.84 g, 6.84 mmol) in DCM (60 mL) was added a solution of HOBt (0.92 g, 6.84 mmol) in DMF (5 mL). DIPCDI (1.05 mL, 6.84 mmol) was added, the reaction mixture was stirred for 2 h at 23 C, Et20 (150 mL) was added, and the solid obtained was filtrated in a filter plate under vacuum to obtain Compound 11 (1 .31 g, 67%).1H NMR (500 MHz, DMSO-d6): delta 9.88 (s, 1 H), 8.03 (d, J = 7.6 Hz, 1 H), 7.77 (dd, J = 12.2, 8.5 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.99 (s, 3H), 6.01 -5.92 (m, 1 H), 5.39 (s, 2H), 5.07 (s, 1 H), 4.41 (s, 2H), 4.39-4.31 (m, 1 H), 4.23- 4.12 (m, 1 H), 3.36 (t, J = 7.0 Hz, 2H), 3.06-2.97 (m, 1 H), 2.96-2.90 (m, 1 H), 2.22-2.03 (m, 2H), 2.01 -1 .88 (m, 1 H), 1 .76-1.62 (m, 1 H), 1 .63-1 .28 (m, 6H), 1 .25-1.1 1 (m, 2H), 0.84 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H).ESI-MS m/z: Calcd. for C28H4oN607: 572.3. Found: 573.3 (M+H)+. |
67% | With benzotriazol-1-ol; diisopropyl-carbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 23℃; for 2h; | To a solution of LIN 1-1 (1.6 g, 3.42 mmol) and 4-aminobenzyl alcohol (PABOH) (0.84 g, 6.84 mmol) in DCM (60 mL) was added a solution of HOBt (0.92 g, 6.84 mmol) in DMF (5 mL). DIPCDI (1.05 mL, 6.84 mmol) was added, the reaction mixture was stirred for 2 h at 23 SC, Et20 (150 mL) was added, and the solid obtained was filtrated in a filter plate under vacuum to obtain LIN 1-2 (1.31 g, 67%). (1570) 1H NMR (500 MHz, DMSO-ofe): d 9.88 (s, 1H), 8.03 (d, J= 7.6 Hz, 1H), 7.77 (dd, J= 12.2, 8.5 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 2H), 7.21 (d, J= 8.2 Hz, 2H), 6.99 (s, 3H), 6.01-5.92 (m, 1H), 5.39 (s, 2H), 5.07 (s, 1H), 4.41 (s, 2H), 4.39-4.31 (m, 1H), 4.23-4.12 (m, 1H), 3.36 (t, J= 7.0 Hz, 2H), 3.06-2.97 (m, 1H), 2.96-2.90 (m, 1H), 2.22-2.03 (m, 2H), 2.01-1.88 (m, 1H), 1.76- 1.62 (m, 1 H), 1.63-1.28 (m, 6H), 1.25-1.11 (m, 2H), 0.84 (d, J= 6.9 Hz, 3H), 0.81 (d, J= 6.8 Hz, 3H). (1571) ESI-MS m/z : Calcd. for C28H40N6O7: 572.3. Found: 573.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.27 g | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In tetrahydrofuran; at 20℃; | A solution of <strong>[87512-31-0]Fmoc-Ala-Ala-OH</strong> (1 g, 2.61 mmol, Eq:1.00) and (4-aminophenyl)methanol (483 mg, 3.92 mmol, Eq: 1.5) in THF (20 ml) was treated with EEDQ (970 mg, 3.92 mmol, Eq: 1 .5). The solution was stirred over night at room temperature. The mixture was diluted with 10% 2-propanol/ethyl acetate (100 mE) and the solution was washed with KHSO4 5%/K2504 10% (2x), water (lx) and brine (lx),sonicated in diethyl ether for several minutes and the solidwas collected by filtration to obtain the product (1.27 g, 1.2mmol) as light brown solid. MS (ISP): (M+H) 488.3.dried over Mg504 and evaporated in vacuo. The residue was sonicated in diethyl ether for several minutes and the solidwas collected by filtration to obtain the product (1.27 g, 1.2mmol) as light brown solid. MS (ISP): (M+H) 488.3. |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 48h; | N-Ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ) (6.21 g) was added to a solution of Example 2.3.1 (3.2 g) and 4-aminobenzyl alcohol ( 1.546 g) in 50 mL of 2: 1 dichloromethane: methanol. The reaction was stirred at room temperature for 2 days. The solvent was concentrated under vacuum. The residue was triturated with 75 mL of ethyl acetate, and the solid was collected by filtration, and dried under vacuum to yield the title compound, which was used in the next step without further purification. MS (ESI) m/e 488.0 (M+H)+. | |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 48h; | N-Ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline (EEDQ) (6.21 g) was added to a solution of Example 2.3.1(3.2 g) and 4-arninobenzyl alcohol (1.546 g) in 50 niL of 2:1dichloromethane:methanol. The reaction was stirred at room temperature for 2 days. The solvent was concentrated under vacuum. The residue was triturated with 75 mL of ethyl acetate, and the solid was collected by filtration, and dried under vacuum to yield the title compound, which was used in the next step without further purification. MS (ESI) rn/c 488.0 (M+H)t |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 48h; | N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (6.21 g) was added to a solution of Example 2.3.1 (3.2 g) and 4-aminobenzyl alcohol (1.546 g) in 50 mL of 2:1 dichloromethane:methanol. The reaction was stirred at room temperature for 2 days. The solvent was concentrated under vacuum. The residue was triturated with 75 mL of ethyl acetate, and the solid was collected by filtration, and dried under vacuum to yield the title compound, which was used in the next step without further purification. MS (ESI) m/e 488.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With ammonium hydroxide; potassium phosphate In dimethyl sulfoxide at 80℃; UV-irradiation; | |
91% | With ammonium hydroxide; potassium phosphate; copper(l) iodide; C17H16N2O3 In dimethyl sulfoxide at 110℃; for 24h; Schlenk technique; Inert atmosphere; | 5 Example 5. Example 5. Synthesis of (4-aminophenyl)methanol Chlorobenzyl alcohol (0.5 mmol), ammonia source (0.75 mmol), copper salt catalyst (0.05 mmol), ligand (0.05 mmol) and base (0.5 mmol) were added into a 10 mL Schlenk tube. The tube was then evacuated and filled with argon for three times, and then 0.5 mL of solvent was added. The reaction mixture was homogeneously stirred at 110° C. for 24 hours. After cooling, the mixture was filtered through silica gel and diatomite plug. The filtrate was concentrated and purified by column chromatography to give the product (4-aminophenyl) methanol (light yellow solid). 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J=8.3 Hz, 2H), 6.62 (d, J=8.3 Hz, 2H), 4.49 (s, 2H), 3.22 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 145.9, 131.0, 128.7, 115.1, 65.1; LC-MS (ESI, m/z): 124.1 (M+H)+. |
90% | With ammonium hydroxide; potassium phosphate; copper(l) iodide; N<SUP>1</SUP>,N<SUP>2</SUP>-bis(2,4,6-trimethoxyphenyl)oxalamide In dimethyl sulfoxide at 110℃; for 12h; Inert atmosphere; Schlenk technique; | 8 Example 8 Example 8 Synthesis of (4-aminophenyl)methanol No.32 Chlorobenzyl alcohol (0.5 mmol), ammonia source (0.75 mmol), copper salt catalyst (0.05 mmol), ligand (0.05 mmol) and base (0.5 mmol) were added into a 10 mL of Schlenk tube. The tube was then evacuated and backfilled with argon (this sequence was repeated three times), and then 0.5 mL of solvent was added. The reaction mixture was stirred well at 110°C. for 12 hours. After cooling, the mixture was filtered through silica gel and celite. The filtrate was concentrated and purified by column chromatography to give the product No.33 (4-aminophenyl) methanol (light yellow solid). 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J=8.3 Hz, 2H), 6.62 (d, J=8.3 Hz, 2H), 4.49 (s, 2H), 3.22 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 145.9, 131.0, 128.7, 115.1, 65.1; LC-MS (ESI, m/z): 124.1 (M+H)+. |
87% | With ammonium hydroxide; potassium phosphate; copper(l) iodide; N1,N2-bis(5-methyl-[1,1'-biphenyl]-2-yl)oxalamide In water; dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In tetrahydrofuran; water; at 20℃; for 48h; | Example 2 Preparation ofN-Fmoc-Asn-PAB-OH [2] A solution of N -Fmoc-Asn (1.77 g, 5.0 mmoles), p-aminobenzyl alcohol (0.86 g, 7.0 mmoles) and EEDQ (1.48 g, 6 mmoles) in THF/H20 (100/20 mL) were stirred at room temperature overnight. Additional amount of EEDQ (0.61 g, 2.5 mmoles) was added and stirred for another 24 hours. THF was removed by concentration and the residue suspension was diluted with NaOH/NaHC03 aqueous solution (2/8 g, 200 mL) and stirred for 3 hours. The precipitate was collected by filtration, rinsed with water and re-suspended in 10%> citric acid (150 mL). Precipitate was collected by filtration, rinsed with 10% citric acid followed by de-salt water and dried in vacuum. The above obtained solid was triturated in ethyl acetate (100 mL). Solid was collected by filtration and dried in vacuum to give an off-white product (0.95 g, 40%> yield). LC/MS: (MH)+ = 460 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; | Generalprocedure of the preparation of compound 10a to 10m General procedure: To a mixture ofn-aminobenzyl alcohol (1.0equiv.) in THF (5-10 ml) was added X-phenyl isocynate (1.1 equiv.) undernitrogen atmosphere. After stirring for 30 min at RT, the reaction mixture wasextract with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was washedwith n-hexane and CHCl3 toafford the benzyl alcohol compounds (this product was used in the next stepwithout further purification). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 0℃; for 18h; | Compound 68 A solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid (5 g, 16.1 mmol) and (4-aminophenyl)methanol (2.77 g, 22.5 mmol, 1.4 eq) in DCM (90 ml) and MeOH (30 ml) was cooled to 0°C, ethyl 2-ethoxyquinoline-l(2H)-carboxylate (7.94 g, 32.1 mmol, 2 eq) was added and stirred for 18 hrs. The mixture was concentrated in vacuo, stirred in ether (100 ml) and filtered to yield (S)-(9H-fluoren-9-yl)methyl l-(4- (hydroxymethyl)phenylamino)-l-oxopropan-2-ylcarbamate (6 g, 14.41 mmol, 90%) as an off white solid.1H NMR (DMSO-d6, 400 MHz): δ = 1.32 (3H, d, CH3,Ala), 4.17-4.29 (4H, m, a-CHAla,CHFmoc, CH2Fmoc ), 4.44 (2H, s, ArCH2), 7.24-7.90 (13H, m, CHArFmoc, H2, H3, NHAla), 9.95(1H, s, NHPABA).13C NMR (DMSO-d6, 100 MHz): δ = 18.1 (CH3Ala), 46.6 (CFmoc), 50.7 (a-CHAla), 62.6 (CH2), 65.6 (CH2 Fmoc), 118.9 (C2), 120.1 (CHFmoc), 125.3 (CHFmoc), 126.9 (CHFmoc), 127.1 (C3), 127.6 (CHFmoc), 137.4, 137.6 (C1, C4), 140.7 (CFmoc), 143.8 (CFmoc), 143.9 (CFmoc), 155.8 (C=OFmoc), 171.4 (C=OAla). MS (ESI) m z; calculated: 417.18 [M+H]+, found: 417.48 [M+H]+ |
89% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; | 9 Example 9 - Compound 26 A solution of compound 19a (Bachem, 7.5 g, 24.09 mmol) and (4-aminophenyl)- methanol 19b (Aldrich, 3.86 g, 31.3 mmol) in anhydrous DCM (Acros, 50 mL) and anhydrous methanol (Acros, 50 mL) was prepared. 2-Ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline ("EEDQ," Bachem, 8.94 g, 36.1 mmol) was added. The reaction mixture was stirred at RT overnight. LCMS analysis showed the reaction was almost complete. The reaction mixture was diluted with EtOAc (400 mL) and the resultant solution was washed with water and brine. The organic phases were dried over anhydrous Na2S04 and concentrated under vacuum to 100 mL volume. The precipitated white solid was collected by filtration and air dried over a weekend to yield compound 20 (white solid, 8.9 g, 21.37 mmol, 89%). ESI-LCMS (M+H): 417.1. |
81% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In acetonitrile at 25℃; for 24h; |
75% | Stage #1: N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 4-aminobenzenemethanol In methanol; dichloromethane at 20℃; for 1h; | |
75% | In methanol; dichloromethane at 20℃; for 12h; Inert atmosphere; | xiii To a stirred solution of compound 1a (5.000 g, 16.06 mmol) in DCM (50 mL) and MeOH (10 mL) was added EEDQ (7.943 g, 32.12 mmol). After it was stirred for 10 min, compound 2a (2.967 g, 24.1 mmol) was added under N2 at 20 °C. After the mixture was stirred at 20 °C for 12 h, it was concentrated, and washed by methyl tert-butyl ether (20 mL x 3) and DCM (20 mL) to afford compound 3a (5.000 g, 75%) as a white solid. LCMS(5-95, AB, l.5min): RT=0.876 min, m/z = 439.2 [M+23]+; NMR (400 MHz, DMSO-d6) d 9.92 (s, 1H), 7.85 (d, J= 7.6 Hz, 2 H), 7.73 - 7.62 (m, 3 H), 7.51 (d, J= 8.4 Hz, 2 H), 7.38-7.19 (m, 6 H), 5.08 (t, J= 5.6 Hz, 1H), 4.39 (d, J= 5.6 Hz, 2 H), 4.29 - 4.21 (m, 2 H), 4.18 - 4.15 (m, 2 H), 1.28 - 1.23 (m, 3 H). |
75.06% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; | I-15.1 Step 1. Synthesis of (9H-fluoren-9-yl)methyl (S)-(l-((4-(hydroxymethyl)phenyl)amino)-l-oxopropan-2-yl)carbamate I-15b Into a 500-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of argon, was placed a solution of (2S)-2-[[(9H-fluoren-9- ylmethoxy)carbonyl]amino]propanoic acid (35.49 g, 114.003 mmol, 1.20 eq) and EDCI (27.32 g, 142.513 mmol, 1.50 eq) in THF (150 mL), p-aminobenzylalcohol (11.7 g, 95.002 mmol, 1.00 equiv) in THF (150 mF) was added dropwise. The resulting solution was stirred for 2 hours at room temperature, quenched by the addition of 500 mF of saturated NaHCO3solution and extracted with 2x500 mF of ethyl acetate. The combined organic layers were washed with 2 x500 ml of brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 29.7 g (75.06%) of 9H-fluoren-9-ylmethyl N-[(lS)-l-[[4- (hydroxymethyl)phenyl] carbamoyl] ethyl] carbamate as a solid. LC-MS (ES, m/z): 417.05[M+H]+. |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; | 2.21.1 2.21.1. (S)-(9H-fluoren-9-yl)methyl (l-((4- (hydroxymethyl)phenyl) amino-l-oxopropan-2-yl)carbamate To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (50 g) in methanol (400 mL) and dichloromethane (400 mL) was added (4-aminophenyl)methanol (23.73 g) and ethyl 2-ethoxyquinoline-l(2H)-carboxylate (79 g), and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was washed by dichloromethane to give the title compound. | |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; | 2.21.1 2.21.1. (S)-(9H-fluoren-9-yl)methyl (1-((4-(hydroxymethyl)phenyl) amino-1-oxopropan-2-yl)carbamate To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (50 g) inmethanol (400 mL) and dichloromethane (400 mL) was added (4-aminophenyl)methanol (23.73 g)and ethyl 2-ethoxyquinoline- 1 (2H)-carboxylate (79 g), and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was washed by dichloromethane to give the title compound. | |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol at 20℃; | 2.21.1 2.21.1. (S)-(9H-fluoren-9-yl)methyl (1-((4-(hydroxymethyl)phenyl) amino-1-oxopropan-2-yl)carbamate To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (50 g) in methanol (400 mL) and dichloromethane (400 mL) was added (4-aminophenyl)methanol (23.73 g) and ethyl 2-ethoxyquinoline-1(2H)-carboxylate (79 g), and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was washed by dichloromethane to give the title compound. | |
330 mg | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane Inert atmosphere; | |
1.8 g | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane at 20℃; for 3h; | 13.1 Step 1: Preparation of (S)-(9H-fluoren-9-yl)-methyl(1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropyl-2-yl)carbamate. At room temperature, 2-ethoxy-1-ethoxycarboxyl-1,2-dihydroquinoline (1.31 g, 5.30 mmol) and p-aminobenzyl alcohol (593 mg, 4.82 mmol) were added to a solution of the compound 30-1 (1.5 g, 4.82 mmol) in dichloromethane (35 mL) and reacted for 3 hours under stirring. Purification was performed on silica gel column chromatography to obtain the title compound (1.8 g). [0348] ESI-MS (m/z): 417.2 [M+H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: (1.30 g, 6.49 mmol) of 4-(Methylsulfonyl)benzoic acid (1a) was mixed with (4.67 g, 2.83 mL, 38.9 mmol) of thionyl chloride in anhydrous THF (7 mL) under argon in a 48 mL HW pressure vessel. After sonication in water bath at 65 C for 75-90 min. the solvent was reduced under vacuum, dry ether was added under argon, followed by removing the solvent again under vacuum. The resulted product was dissolved in anhydrous THF (5 mL) and added slowly to a mixture, in ice bath, of triethylamine (1.97 g, 1.40 mL, 19.5 mmol) and 4-substituted aniline 2a (0.779 g, 7.14 mmol), 2b (0.880 g, 7.14 mmol), 2c (0.980 g, 7.14 mmol), under argon. After stirring for 24 h at r. t., solvent was removed under vacuum and the crude solid was sonicated with a mixture of diethyl ether and THF (9:1) (50 mL) followed by suction filtration and additional wash with Et2O (2 x 50 mL) to offer the desired amide in a pure form 3a? (1.55 g, 5.32 mmol, 82%), 3b? (1.59 g, 5.19 mmol, 80%), and 3c? (1.76 g, 5.52 mmol, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | General procedure: (1.39 g, 6.46 mmol) of 2-(4-(methylsulfonyl)phenyl)acetic acid was mixed with (1.26 g, 7.79 mmol) of N,N'-carbonyldiimidazole (CDI) in anhydrous THF (7 mL) under argon in a 48 mL HW pressure vessel. After the evolving of the CO2 gas stopped, the reaction stirred for 60 min at r.t. followed by the addition of the 4-substituted aniline 2a (0.850 g, 7.79 mmol), 2b (0.959 g, 7.79 mmol), 2c (1.07 g, 7.79 mmol), dissolved in 3 mL of anhydrous THF at r.t. under argon. The reaction vessel was closed and stirred at r.t. for 48 h. Solvent was removed under vacuum and the crude solid was sonicated with a mixture of diethyl ether and THF (9:1) (50 mL) followed by suction filtration and additional wash with Et2O (2x50 mL) to offer the desired amide in a pure form 3g (1.64 g, 5.39 mmol, 83%), 3h (1.62 g, 5.06 mmol, 78%), and 3i (1.88 g, 5.64 mmol, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In dichloromethane; at 20℃; for 12h; | A solution of <strong>[145038-49-9]Fmoc-Glu-OMe</strong> (II, 425 mg, 1 mmol) and 4-aminobenzyl alcohol (III, 123 mg, 1 mmol) was dissolved in 20 ml of methylene chloride,2-ethoxy-1-ethoxycarbonyl-12-dihydroquinoline (EEDQ) (296 mg, 1.2 mmol) was added,The reaction was stirred at room temperature for 12 hours.The reaction solution was diluted with 50 ml of methylene chloride,The reaction was quenched by the addition of 1 N of dilute hydrochloric acid.The organic layer was washed successively with saturated sodium bicarbonate,And saturated saline, the wash 3 times,Dried over anhydrous sodium sulfate,Filtration, concentration,Silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1)To give light yellow solid IV (424 mg, 80%). |
74% | With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h; | A GGT targeted prodrug was synthesized via the following Scheme 3. Fmoc and methyl protected L-glutamic acid was coupled with p-aminobenzyl alcohol from gamma-carboxylic acid followed by bromination. The brominated intermediate was then coupled to diethyldithiocarbamate which was then deprotected to yield the final desired product. A) p-Aminobenzyl alcohol, HBTU, 4percent NMM in DMF, 3h, rt, 74percent; B) PBr3, Dry THF, 3 h, 0 °C, 43percent; C)(i) Sodium diethyldithiocarbamate, Dry THF, 12 h, rt , 48percent (ii) LiOH in THF and H20, 30 min, rt, D) 20percent piperidine in DMF, 1 h, rt, 48percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.985 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 4.0h; | Cbz-Arg-OH (3.448 g, 10 mmol), HOBT (1.531 g, 10 mmol), 4-aminobenzylalcohol (1.232 g, 10 mmol) and EDCl (2.300 g, 10 mmol) was dissolved in 50 mL DMF. 4.0 hour later, the solvent DMF was removed by high vacuum. The residue was separated by column chromatography 120 g silica gel (gradient: methanol/dichloromethane 5% to 34%), then solvent was removed by rotavap and got 3.985 g light brown solid. 1H NMR (500 MHz, DMSO) delta 10.20 (s, 1H), 7.87 (t, J=5.4 Hz, 1H), 7.61 (dd, J=14.4, 8.1 Hz, 3H), 7.39-7.29 (m, 5H), 7.24 (d, J=8.4 Hz, 2H), 5.14 (t, J=5.7 Hz, 1H), 5.08-4.95 (m, 2H), 4.43 (d, J=5.6 Hz, 2H), 4.19 (dd, J=13.7, 8.3 Hz, 1H), 3.12 (dd, J=12.8, 6.5 Hz, 2H), 1.84-1.70 (m, 1H), 1.69-1.41 (m, 3H). 13C NMR (126 MHz, DMSO) delta 170.65, 156.92, 156.03, 137.54, 137.46, 136.96, 128.35, 127.80, 127.71, 126.85, 118.97, 65.46, 62.57, 54.92, 40.13, 28.94, 25.21. HRMS (ESI) calcd for C21H28N5O4+ (MH+) 414.2136. found 414.2149. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | (2) 2460 mg 4-aminophenylmethanol (20mmol) dissolved in 14 ml 1,4-dioxane, 14 ml water and 22 ml 1M sodium hydroxide solution mixed solution. Cool to 0 C. Add 6540 mg di-tert-butyl dicarbonate (30mmol). Stir at room temperature for 6 hours, decompression turns on lathe does organic solvent, ethyl acetate or methylene chloride extraction, the organic phase water, saturated sodium chloride solution each washed, dried with anhydrous sodium sulfate, the solvent is removed and steaming and; then, add 20 ml chloroform, batchwise add 4696 mg manganese dioxide (54mmol). At room temperature, stir the reaction for 12 hours, after the end of the reaction, filtration, turns on lathe does under reduced pressure, the resulting solid by silica gel column chromatography purification (petroleum ether: ethyl acetate, V/V=10:1), to obtain white solid product 4 - uncle Ding Yangtang amino formaldehyde 3933 mg (yield 89%), used directly for the next step reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran at 20℃; | |
82% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In 1,4-dioxane at 20℃; for 72h; | 8 To a solution of 4-aminobenzyl alcohol (5 g, 40.6 mmol) and N-(tert- butoxycarbonyl)-L-alanine (9.8 g, 52 mmol) in anhydrous dioxane (60 ml) was added N-ethoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline (13 g, 54 mmol) and the reaction mixture was stirred for 3 days at room temperature. The reaction mixture was diluted with water (600 ml), washed with petroleum ether/ methyl tert-butyl ether (100 ml, 1 :1 ) and ethyl acetate (3 x 150 ml). The combined ethyl acetate extracts were dried (sodium sulfate), concentrated in vacuum and crystallized from toluene to yield N- Boc-L-alanyl(4-(hydroxymethyl)phenyl)amide 8 (9.8 g, 82 %, 33.3 mmol) as a waxy solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .24 (d, J= 7.1 Hz, 3 H) 1 .37 (s, 9 H) 4.09 (m, 1 H) 4.42 (d, J=5.5 Hz, 2 H) 5.08 (t, J=5.6 Hz, 1 H) 7.03 (d, J=7.2 Hz, 1 H) 7.22 (m, J=8.5 Hz, 2 H) 7.53 (m, J=8.5 Hz, 2 H) 9.84 (s, 1 H) |
82% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran at 0 - 20℃; Inert atmosphere; |
70% | Stage #1: L-N-Boc-Ala With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 0 - 20℃; for 1.2h; Stage #2: 4-aminobenzenemethanol In dichloromethane at 20℃; for 25h; | 1.2 2) Synthesis of compound 4 At 0°C, dissolve Boc-L-alanine (0.17 g, 0.9 mmol), HATU (0.42 g, 1.1 mmol) and DIPEA (0.37 mL, 2.3 mmol) in anhydrous dichloromethane solution (30 mL ), stirring at room temperature for 1.2 hours,Add p-aminobenzyl alcohol (0.14 g, 1.1 mmol) to the reaction mixture, and stir for further 25 hours at room temperature.The solvent was evaporated under reduced pressure, and column purification (dichloromethane/methanol=20/1) was used to obtain compound 4 with a yield of 70%. |
Stage #1: L-N-Boc-Ala With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 4-aminobenzenemethanol In N,N-dimethyl-formamide at 20℃; | Synthesis of compound 2. To a solution of (tert-butoxycarbonyl)-L-alanine (567.3S4mg, 3.0 mmol) in DMF (15 mL), HATU (1140.6 mg, 3.0 mmol) and DIPEA (387.9mg, 3.0 mmol) was added, which was stirred at 0 °C for 30 min. Then, a solution of 4-Aminobenzyl alcohol (369.5 mg, 3.0 mmol) in DMF (5 mL) was added, and the mixture was stirred at room temperature overnight. Then the reaction solution was diluted with 150 mL CH2Cl2 and washed with water and brine. The organic phase was dried over MgSO4, after removing the solvent by reduced pressure distillation, and crude product 1 was obtained, which was used for the next step without further purification. The crude compound 1 was dissolved in CH2Cl2 (50 mL), and a solutionof PBr3 (812.1 mg, 3.0 mmol) in CH2Cl2 (5 mL) was added dropwise, and the mixture was stirred at 0 °C for 45 min. Then the reaction solution was washed with water and brine, and the organic solvent was removed by reduced pressure distillation. The residue was further purified by a silica gel column chromatograph usingCH2Cl2/MeOH (40/1 v/v) as the mobile phase to afford compound 2 as a white solid(396.3 mg, yield: 37.1%). 1H NMR (500 MHz, CDCl3) δ 8.70 (s, 1H), 7.48 (d, J = 8.4Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 5.11 (d, J = 5.5 Hz, 1H), 4.46 (s, 2H), 4.34 (s, 1H),1.46 (s, 9H), 1.43 (d, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 170.99, 156.29,138.03, 133.43, 129.79, 119.90, 80.82, 50.78, 33.44, 28.31, 17.34. HRMS (ESInegative) calcd for [M-H+MeOH]- 387.0925, found 387.0927. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In 1,4-dioxane; at 20℃; for 12h; | To a solution of 4-aminobenzyl alcohol (62 g, 504 mmol) and N-(tert- butoxycarbonyl)-L-pyroglutamic acid (1 16 g, 504 mmol) in anhydrous dioxane (500 ml) was added N-ethoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline (130 g, 526 mmol) and the reaction mixture was stirred for 12 hours at room temperature. To complete precipitation the reaction mixture was cooled to 10C. Compound 10 (1 14 g, 68 %, 340 mmol) was collected by suction, washed with cold dioxane and dried in vacuum. 1H NMR (400 MHz, DMSO-d6) delta ppm 1 .34 (s, 9 H) 1 .83 - 1 .94 (m, 1 H) 2.23 - 2.26 (m, 1 H) 2.37 - 2.48 (m, 2 H) 4.42 (s, 2 H) 4.63 (dd, J=8.99, 3.61 Hz, 1 H) 5.10 (bt, 1 H) 7.25 (d, J=8.56 Hz, 2 H) 7.53 (d, J=8.44 Hz, 2 H) 10.23 (s, J=4.76 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Sodium nitrite (5.3 g) was dissolved in 30 mL of pure water, and then added to a pure aqueous solution (120 mL) containing 18 mL of concentrated hydrochloric acid containing 4-aminobenzyl alcohol (8.2 g), and reacted at room temperature for 20 minutes to obtain a reaction. The solution was added to an ethanol solution containing <strong>[553-27-5]N,N-bis(2-chloroethyl)aniline</strong>. After reacting for 2 hours, the obtained reaction solution was diluted with dichloromethane (500 mL) and washed twice with water. The resulting organic phase was dried over Na 2 SO 4 overnight. the obtained product was subjected to rotary evaporation and concentration, and then column chromatography separation to obtain a raw material 3,. The eluent was a methanol-dichloromethane mixture (the ratio of methanol to dichloromethane was 1:13). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
750 mg | Fmoc-Lys(mmt)-OH (2g, 3.2mmol, 1eq) was added to the vial PABA (788.16 mg, 6.4 mmol, 2 eq), HATU (1.34g, 3.52mmol, 1.1eq), DIEA (1.24g, 9.6mmol, 3eq) and 20ml DMF, nitrogen protection after stirring and dissolving,25 C reaction point plate detection, lysine reaction is complete. 200 ml of water was added to the reaction solution, and a large amount of solid was precipitated, and EA (60 ml x 3) was extracted.The organic phase was washed three times with brine and dried over anhydrous sodium sulfate.It was dried to a yellow oil of 2.85 g. The upper intermediate was dissolved in 20 ml of diethylamine.Nitrogen protection, 25 C reaction; Point board detection, the raw material reaction is complete.The solvent was sparged and dissolved in EtOAc (3 mL).Column chromatography purification: Gradient elution with DCM: MeOH = 100:1 to 50:1 as mobile phase to afford 750 mg of product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A/-Ethoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline (EEDQ, 741 mg, 3.0 mmol) was added to anhydrous CH2CI2 dissolved Cbz-Gly-Pro-OH (470 mg, 1.54 mmol) under N2 atmosphere and the reaction mixture was stirred for 20 min. Then p-aminobenzyl alcohol (369 mg, 3 mmol) dissolved in CH2CI2 was added via a syringe and stirred overnight at room temperature. The pure product 1-1 (525 mg, 83%) was obtained after HPLC purification. MS of compound 1-1 : calculated for C22H25N3Na05, [(M+Na)+]: 434.17; obsvd. ESI-MS: m/z 434.17. 1H NMR of compound 1 -1 (d4-CD3OD, 400 MHz) d (ppm): 7.53 (d, J = 12.0 Hz, 2 H), 7.28-7.37 (m, 7 H), 5.10 (s, 2 H), 4.56 (m, 3 H), 4.00 (m, 2 H), 3.61-3.67 (m, 2 H), 1.94-2.26 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; | Specific procedure: Intermediate 1 (1 g) was dissolved in THF (10 mL), p-aminobenzyl alcohol (0.64 mg),EDCI (1.475g) and DIPEA (1.28mL) were added in sequence and stirred at room temperature for 1-2 hours.After the reaction is completed, the mixture is washed with water and brine, and the organic layer is combined and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure to give a dark brown intermediate 2, which was directly reacted. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 10-methyl-9-(2,4,6-trimethylphenyl) acridinium tetrafluoroborate; In acetonitrile; at 20℃; for 5h;Irradiation; | In air, p-aminobenzyl alcohol (0.2 mmol, 27 mg) was dissolved in acetonitrile (2 mL), and then Mes-Acr-MeBF4 (2 mol%, 2 mg) and thioacetic acid (0.4 mmol, 30 mg) were added. The mixture was stirred for 5 hours at room temperature under a 36W blue LED. The mixture was quenched with water (2 mL) and then extracted with EtOAc (3 x 4 mL). The organic phase was washed with brine, dried over Na 2 SO 4 and spin-dried, and then separated by column chromatography to obtain 26 mg of a white solid product with a yield of 79%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methoxymorpholinium chloride In tetrahydrofuran at 40℃; for 2h; Inert atmosphere; | 1 Synthesis of 2-(4-fluorophenyl)-N-(4-(hydroxymethyl)phenyl)acetamide (Compound ts10) Under a nitrogen atmosphere, THF (9.7 mL) was added to a mixture of 2-(4-fluorophenyl)acetic acid (300 mg, 1.95 mmol), 4-aminophenylmethanol (264 mg, 2.14 mmol), and DMT-MM (646 mg, 2.34 mmol), and then this was stirred at 40° C. for two hours. The reaction solution was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile) to give 2-(4-fluorophenyl)-N-(4-(hydroxymethyl)phenyl)acetamide (Compound ts10) (400.0 mg, 79.0%). LCMS (ESI) m/z=260 (M+H)+ Retention time: 0.55 minutes (analysis condition SQDFA05) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 90℃; for 18h; | Compound <strong>[372118-01-9]4,6-dichloropyridazine-3-carboxylic acid methyl ester</strong> 1a (800 mg, 3.88 mmol), 4-aminobenzyl alcohol (477 mg, 3.88 mmol), diisopropylethylamine (500 mg, 3.88 mmol) Mix with ethanol (20 mL), heat to 90 C and stir for 18 hours.After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 19/1).The target product 6-chloro-4-((4- (hydroxymethyl) phenyl) amino) pyridazine-3-carboxylic acid methyl ester 49a (500 mg, yellow solid) was obtained in a yield of 44%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With ammonium hydroxide; copper(l) iodide; N,N'-bis(3,5-dimethoxyphenyl)cyclopentane-1,1-dicarboxamide; caesium carbonate In dimethyl sulfoxide at 90℃; for 24h; Inert atmosphere; Sealed tube; | General Procedure B for the Coupling of Aryl and Heteroaryl Bromides with Aqueous Ammonia General procedure: A 10 mL flask was charged with a magnetic stir bar, CuI (19 mg,10 mol%), L2 (86 mg, 20 mol%), Cs2CO3 (651 mg, 2 mmol) and solid aryl iodides (1.0 mmol). The tube was evacuated and backfilled with argon (this procedure was repeated three times). Under a counter flow of Argon, DMSO (1.0 mL),1.0 mmol aryl iodides (if liquid), 0.9 mL (12.0 mmol) aqueous ammonia (28%) were added by syringe slowly. The reaction mixture was allowed to stir under argon at 90°C for 24 h. After cooling to room temperature, the mixture was diluted with 30 ml dichloromethane and passed through a fritted glass filter, the filter cake was further washed with 15 ml dichloromethane, dried over Na2SO4, filtered and the most solvent was removed under vacuum. The residue was purified by column chromatography on silica gel with an eluent of petroleum ether and ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
325 mg | Stage #1: 3-acetyl-2-naphthol With water; sodium hydroxide In ethanol at 20℃; for 0.5h; Stage #2: 4-(hydroxylmethyl)benzaldehyde In ethanol at 20℃; for 5h; Stage #3: 4-aminobenzenemethanol; 2-nitrophenylmethyl bromide; Methacryloyl chloride Further stages; | 1.1-1 Preparation method Weigh 1 (1g, 5.37mmol), add 15mL ethanol to form a suspension, add sodium hydroxide aqueous solution (5.4mL, 5M), stir at room temperature for 30min, add p-hydroxymethyl benzaldehyde (748mg, 5.5mmol) In the reaction flask, stir at room temperature for 5 hours. After the reaction is completed, cool to 0°C, add 2mL 30% hydrogen peroxide dropwise and react overnight, acidify the pH to 6.5 with 0.5M HCl, form a yellow precipitate, and filter with suction to obtain the product; The product (288mg, 1mmol), potassium carbonate (140mg, 1.0mmol), o-nitrobenzyl bromide (258mg, 1.2mmol) was dissolved in 10mL DMF, the mixture was stirred at room temperature for 12h, after the reaction, it was precipitated into water and filtered to obtain the product; Take the product from the previous step (453 mg, 1 mmol) and pyridinium chlorochromate (620 mg, 1.2 mmol), add 55 mL of anhydrous dichloromethane to dissolve and clarify, react overnight at room temperature, filter and wash three times with suction, and recrystallize to obtain a yellow product; The aldehyde-based product (450 mg, 1 mmol) obtained in one step was added to 20 mL of THF, 15 mL of ethanol was dissolved and clarified, and p-aminobenzyl alcohol (563 mg, 3.68 mmol) was added, and reacted at room temperature overnight, that is, a solid precipitated out. The reaction solution was filtered with suction to obtain a filter cake of 300 mg. Dissolve in dichloromethane, add 266mg of sodium cyanoborohydride, react for 2h to remove the solvent by rotary evaporation, add 10mL of THF to dissolve, add 5mL of glacial acetic acid, then add 55mg of sodium nitrite, react overnight, column chromatography to obtain a yellow product .Weigh the precursor product (293mg, 0.5mmol) and dissolve it in 30mL of anhydrous dichloromethane, add anhydrous triethylamine (100mg, 1mmol), add methacrylic acid chloride (105mg, 1mmol), react at room temperature for 6h, wash the column with water Chromatography yielded 325 mg of a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: N-tert-butoxycarbonyl-L-alanyl-L-alanine With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran for 0.166667h; Inert atmosphere; Cooling with ice; Stage #2: 4-aminobenzenemethanol With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 25℃; for 12h; Inert atmosphere; | |
78.3% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane at 20℃; for 40h; | 1.A (A) tert-butyl ((S)-l-(((S)-l-((4-(hydroxymethyl)phenyl)amino)-l-oxopropan-2-yl)amino)-l-oxopropan-2- yl)carbamate, intermediate- 1 (tert-Butoxycarbonyl)-L-αlanyl-L-αlanine (2440 mg, 9.09 mmol, Chem-Impex) and 4- aminobenzyl alcohol (1154 mg, 9.09 mmoL) in DCM (50 mL) was treated with N-ethoxycarbonyl- 2ethoxy-1,2-dihydroquinoline (EEDQ, 2498 mg, 10.0 mmol) at rt for 40h. The solid was collected by filtration and washed with DCM (3 x lOmL) and dried over vacuum to get the pure product. The filtrate was purified by chromatography on silica gel (0-10% MeOH in DCM) to get another batch of product. Two batches of product were combined as the intermediate- 1 (2600 mg, 78.3%). LCMS (AA): m/z = 366.2 (M+H). Tf NMR (MeOH-d4) d 7.57 (d, J= 8.0 Hz, 2H), 7.30 (d, J= 8.0 Hz, 2H), 4.56 (s, 2H), 4.49-4.45 (m, m), 4.09-4.04 (m, 1H), 1.45 (s, 3H), 1.44 (s, 9H), 1.33 (d, J= 8.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: Fmoc-Pro-OH With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: 4-aminobenzenemethanol In N,N-dimethyl-formamide at 20℃; | 11 Synthesis of (9//-fluoren-9-yl (methyl (2A)-2-((4-(hydroxymethyl)phenyl)carbamoyl)-l l4- pyrrolidine-l-carboxylate Fmoc-Pro-OH (312 mg; 0.92 mmol; 1.0 eq) and HATU (393 mg; 1.01 mmol; 1.1 eq) were dissolved in dry DMF (4 mL) under argon atmosphere and the solution was cooled to 0 °C. DIPEA (505 pL; 2.76 mmol; 3.0 eq) was added dropwise and the mixture was stirred at the same temperature for 15 minutes. 4- aminobenzyl alcohol (226 mg, 1.84 mmol, 2 eq.) was added as a solution in dry DMF. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with AcOEt and washed with aqueous 1M KHSCE, saturated NaHCCE and brine. The pooled organic phases were dried and concentrated under vacuum. The crude was purified via chromatography (DCM/MeOH 99: 1 to 95 :5 in 10 min) to afford the product as a white powder (274 mg; 0.66 mmol; 66% yield). MS(ES+) m/z 443.19 (M+1H)1+ |
Tags: 623-04-1 synthesis path| 623-04-1 SDS| 623-04-1 COA| 623-04-1 purity| 623-04-1 application| 623-04-1 NMR| 623-04-1 COA| 623-04-1 structure
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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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