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CAS No. : | 4246-51-9 | MDL No. : | MFCD00059850 |
Formula : | C10H24N2O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JCEZOHLWDIONSP-UHFFFAOYSA-N |
M.W : | 220.31 | Pubchem ID : | 20239 |
Synonyms : |
PROTAC Linker 24
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 12 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 58.85 |
TPSA : | 79.73 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.62 cm/s |
Log Po/w (iLOGP) : | 2.71 |
Log Po/w (XLOGP3) : | -1.38 |
Log Po/w (WLOGP) : | -0.27 |
Log Po/w (MLOGP) : | -0.65 |
Log Po/w (SILICOS-IT) : | 0.83 |
Consensus Log Po/w : | 0.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.46 |
Solubility : | 629.0 mg/ml ; 2.85 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.21 |
Solubility : | 354.0 mg/ml ; 1.61 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -2.44 |
Solubility : | 0.802 mg/ml ; 0.00364 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.52 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P234-P273-P280-P301+P330+P331-P303+P361+P353-P305+P351+P338 | UN#: | 2735 |
Hazard Statements: | H314-H290-H412 | Packing Group: | Ⅲ |
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 |
---|---|---|
88% | at 0 - 20℃; for 3 h; | To a solution ofamine S8 (20 mL, 91.2 mmol) in CH2Cl2(100 mL) was added a solution of Boc2O (1.99 g, 9.12 mmol) in CH2Cl2(55 mL + 5 mL rinse) dropwise via addition funnel at 0 °C. After the additionwas complete, the reaction mixture was allowed to warm to RT and after 3 h, itwas quenched with H2O (100 mL). Thetwo layers were separated and the organic phase was washed with H2O (3 x 50 mL) andbrine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to give 2.571 g (88percent) of S9 as a colorless liquid.TLC: Rf = 0.14 (10percent MeOH, 0.5percent NH4OHin CH2Cl2)1H-NMR (CDCl3, 400 MHz): δ 5.10 (br s,1H), 3.51–3.64 (m, 12H), 3.61 (s, 4H), 3.21 (m, 2H), 2.79 (t, J = 6.7 Hz, 1H), 1.77–1.68 (m, 4H), 1.42(s, 9H) ppm |
85% | at 20℃; for 12 h; | A solution of di-tert-butyl dicarbonate (Boc2O, 2.75 mmol) in dried DCM (2 mL) was added slowly, drop to drop, to a solution of 4,7,10-trioxatridecane-1,13-diamine (VIII, 6.8 mmol) in DCM (20 mL). The reaction mixture was maintained at rt for 12 h, and then was diluted with water and extracted three times with DCM. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure and thus the mono-blocked derivative H2N-PEG-NH-Boc (IX, 85percent) was produced. 4.6.1 Compound IX Syrup; δH (CDCl3, 400MHz): 5.13 (m, 1H, NH PEG-Boc group), 3.64–3.49 (m, 12H, 6 CH2 PEG group), 3.20 (m, 2H, 1 CH2 PEG group), 2.80 (m, 2H, 1 CH2 PEG group), 1.76–1.69 (m, 4H, 2 CH2 PEG group), 1.41 (s, 9H, 3 CH3 Boc group); δC (CDCl3, 100MHz): 156.2 (CO-Boc), 79.0 (CO-Boc), 70.6, 70.3, 70.2, 69.6 (6C, CH2 PEG group), 39.7, 38.5, 32.9, 29.7 (4C, CH2 PEG group), 28.6 (3 CH3 Boc group). |
82% | With triethylamine In dichloromethane at 20℃; Cooling with ice | To a solution of 3,3'-((oxybis(ethane-2,l-diyl))bis(oxy))bis(propan-1-amine) (10 g, 45 mmol) and triethylamine (4.6 g, 45 mmol) in DCM (150 mL) was added solution of (Boc)20 (5.0 g, 23 mmol) in DCM (100 mL) cooled in an ice-bath and was stirred at rt overnight. The solution was concentrated to dryness and purified by flash column chromatography to give the title compound (5.976 g, 82.00percent yield) as a slight yellow oil. MS (ESI): mass calcd. for ci5H32N2O5, 320.42; m/z found, 321.2 [M+H]+. |
72.2% | With sodium chloride In tetrahydrofuran; methanol | Part C Preparation of N-(3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)(tert-butoxy)formamide A 1 L 3-neck round bottom flask was fitted with a 500 mL addition funnel with nitrogen line, a thermometer, and a mechanical stirrer. The flask was charged with 4,7,10-trioxa-1,13-tridecanediamine (72.5 g, 0.329 mol), anhydrous THF (250 mL), and anhydrous MeOH (100 mL). The addition funnel was charged with a solution of di-tert-butyl dicarbonate (22.4 g, 0.103 mol) in anhydrous THF (100 mL). The contents of the addition funnel were added to the flask with rapid stirring at ambient temperatures over 30 min, causing a slight rise in temperature from 21° C. to 32° C. The reaction was stirred an additional 3 h at ambient temperatures and the solvents were removed under reduced pressure. The resulting thick syrup was taken up in sat. NaCl (1500 mL) and extracted with ether (5*1000 mL). The combined ether extracts were dried (MgSO4) and concentrated to give a colorless oil (29.8 g). A 5.00 g sample of this oil was purified by flash chromatography on silica gel (DCM:MeOH:TEA, 20:15:0.75) to give the title compound as a colorless oil (4.00 g, 72.2percent). 1H NMR (CDCl3): 5.13 (s, 1H), 3.63-3.47 (m, 12H), 3.17 (q, J=6.2 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H), 1.75-1.64 (m, 4H), 1.39 (s, 9H), 1.36 (s, 2H); MS: m/e 321.2 [M+H]. |
72.2% | With sodium chloride In tetrahydrofuran; methanol | Part C Preparation of N-(3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)(tert-butoxy)formamide A 1 L 3-neck round bottom flask was fitted with a 500 mL addition funnel with nitrogen line, a thermometer, and a mechanical stirrer. The flask was charged with 4,7,10-trioxa-1,13-tridecanediamine (72.5 g, 0.329 mol), anhydrous THF (250 mL), and anhydrous MeOH (100 mL). The addition funnel was charged with a solution of di-tert-butyl dicarbonate (22.4 g, 0.103 mol) in anhydrous THF (100 mL). The contents of the addition funnel were added to the flask with rapid stirring at ambient temperatures over 30 min, causing a slight rise in temperature from 21° C. to 32° C. The reaction was stirred an additional 3 h at ambient temperatures and the solvents were removed under reduced pressure. The resulting thick syrup was taken up in sat. NaCl (1500 mL) and extracted with ether (5*1000 mL). The combined ether extracts were dried (MgSO4) and concentrated to give a colorless oil (29.8 g). A 5.00 g sample of this oil was purified by flash chromatography on silica gel (DCM:MeOH:TEA, 20:15:0.75) to give the title compound as a colorless oil (4.00 g, 72.2percent). 1H NMR (CDCl3): 5.13 (s, 1H), 3.63-3.47 (m, 12H), 3.17 (q, J=6.2 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H), 1.75-1.64 (m, 4H), 1.39 (s, 9H), 1.36 (s, 2H); MS: m/e 321.2 [M+H] |
72.2% | With sodium chloride In tetrahydrofuran; methanol | Part C Preparation of N-(3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)(tert-butoxy)formamide A 1 L 3-neck round bottom flask was fitted with a 500 mL addition funnel with nitrogen line, a thermometer, and a mechanical stirrer. The flask was charged with 4,7,10-trioxa-1,13-tridecanediamine (72.5 g, 0.329 mol), anhydrous THF (250 mL), and anhydrous MeOH (100 mL). The addition funnel was charged with a solution of di-tert-butyl dicarbonate (22.4 g, 0.103 mol) in anhydrous THF (100 mL). The contents of the addition funnel were added to the flask with rapid stirring at ambient temperatures over 30 min, causing a slight rise in temperature from 21° C. to 32° C. The reaction was stirred an additional 3 h at ambient temperatures and the solvents were removed under reduced pressure. The resulting thick syrup was taken up in sat. NaCl (1500 mL) and extracted with ether (5*1000 mL). The combined ether extracts were dried (MgSO4) and concentrated to give a colorless oil (29.8 g). A 5.00 g sample of this oil was purified by flash chromatography on silica gel (DCM:MeOH:TEA, 20:15:0.75) to give the title compound as a colorless oil (4.00 g, 72.2percent). 1H NMR (CDCl3): 5.13 (s, 1H), 3.63-3.47 (m, 12H), 3.17 (q, J=6.2 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H), 1.75-1.64 (m, 4H), 1.39 (s, 9H), 1.36 (s, 2H); MS: m/e 321.2 [M+H]. |
49% | at 20℃; for 12 h; | A solution of 4,7,10-trioxa-1,13-tridecanediamine (7.5g, 34.1mmol) in CHCl3 (100mL) was treated with BOC-anhydride (3.7g, 16.9mL). The mixture was stirred at room temperature for 12h. The solvent was removed, and the resulting yellow oil was purified by silica gel flash chromatography to produce the oil 5.5g of tert-butyl (3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)carbamate (4), Yield: 49percent. 1H NMR (CDCl3, 400MHz): δ 5.1 (s, 1H), 3.58–3.50 (m, 12H), 3.21 (d, J=6.9Hz, 2H), 2.79 (t, J=8Hz, 2H), 1.75–1.69 (m, 4H), 1.59 (s, 2H), 1.42 (s, 9H). 13C NMR (CDCl3, 100MHz): δ 155.0, 69.2, 68.9, 66.7, 48.0, 37.6, 30.4, 28.6, 27.3. |
16% | With triethylamine In chloroform at 0℃; for 0.666667 h; | Preparation of compound 69: To a solution of 4,7, 10-trioxa-l, 13-tridecanediamine (2.2 g, 10 mmol) in CHC13 (100 mL) at 0 °C was added Boc20 (2.18 g, 10 mmol) and Et3N (1.4 mL, 10 mmol). The reaction was stirred at 0 °C for 40 min. The reaction was concentrated to give crude product. The crude product was purified by column chromatography using 2-6percent EtOH in CH2C12 to give purified product as slight yellow oil (516 mg, 16percent). Note: the mono- protected amine must be freshly prepared. It undergoes gradual disproportionation upon storage. Analytical data matched that described in /. Am. Chem. Soc. 2003, 125, 2416- 2425. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium tetrahydroborate; In methanol; at 20 - 60℃; for 23h; | In a Schlenk flask containing a solution of 1,13-diamino-4,7,10-trioxatridecan (2 g, 9.08 mmol) in CH3OH (20 mL) benzaldehyde (2.02 g, 19.1 mmol) was added and the mixture was stirred at room temperature for 3 h. Then NaBH4 (1.37 g, 36.3 mmol) was added in small portions. After the complete addition, the reaction was stirred for 2 h at 60 C and then at room temperature for 18 h. The solvent was removed under reduced pressure, the obtained residue was taken up in CH2Cl2 (100 mL), washed with H2O (3 ' 150 mL) and brine (100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography over silica gel (using CH2Cl2/CH3OH as the eluent) to provide 2 (2.27 g, 63%) as an oil.1H NMR (300 MHz, CDCl3): d 7.36-7.21 (m, 10H), 3.80 (s, 4H), 3.62-3.52 (m, 12H), 2.74 (t, J = 6.9 Hz, 4H), 2.59 (s, 2H), 1.86-1.77 (m, 4H). 13C {1H} NMR (75 MHz, CDCl3): d 139.6, 128.2, 128.1, 126.9, 70.4, 70.0, 69.7, 53.6, 46.5, 29.5. ESI-LRMS: for C24H37N2O3+: calcd 401.3 [M+H]+, found 401.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In dichloromethane; at 0 - 20℃; for 3h; | To a solution ofamine S8 (20 mL, 91.2 mmol) in CH2Cl2(100 mL) was added a solution of Boc2O (1.99 g, 9.12 mmol) in CH2Cl2(55 mL + 5 mL rinse) dropwise via addition funnel at 0 C. After the additionwas complete, the reaction mixture was allowed to warm to RT and after 3 h, itwas quenched with H2O (100 mL). Thetwo layers were separated and the organic phase was washed with H2O (3 x 50 mL) andbrine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to give 2.571 g (88%) of S9 as a colorless liquid.TLC: Rf = 0.14 (10% MeOH, 0.5% NH4OHin CH2Cl2)1H-NMR (CDCl3, 400 MHz): delta 5.10 (br s,1H), 3.51-3.64 (m, 12H), 3.61 (s, 4H), 3.21 (m, 2H), 2.79 (t, J = 6.7 Hz, 1H), 1.77-1.68 (m, 4H), 1.42(s, 9H) ppm |
85% | In dichloromethane; at 20℃; for 12h; | A solution of di-tert-butyl dicarbonate (Boc2O, 2.75 mmol) in dried DCM (2 mL) was added slowly, drop to drop, to a solution of 4,7,10-trioxatridecane-1,13-diamine (VIII, 6.8 mmol) in DCM (20 mL). The reaction mixture was maintained at rt for 12 h, and then was diluted with water and extracted three times with DCM. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure and thus the mono-blocked derivative H2N-PEG-NH-Boc (IX, 85%) was produced. 4.6.1 Compound IX Syrup; deltaH (CDCl3, 400MHz): 5.13 (m, 1H, NH PEG-Boc group), 3.64-3.49 (m, 12H, 6 CH2 PEG group), 3.20 (m, 2H, 1 CH2 PEG group), 2.80 (m, 2H, 1 CH2 PEG group), 1.76-1.69 (m, 4H, 2 CH2 PEG group), 1.41 (s, 9H, 3 CH3 Boc group); deltaC (CDCl3, 100MHz): 156.2 (CO-Boc), 79.0 (CO-Boc), 70.6, 70.3, 70.2, 69.6 (6C, CH2 PEG group), 39.7, 38.5, 32.9, 29.7 (4C, CH2 PEG group), 28.6 (3 CH3 Boc group). |
82% | With triethylamine; In dichloromethane; at 20℃;Cooling with ice; | To a solution of 3,3'-((oxybis(ethane-2,l-diyl))bis(oxy))bis(propan-1-amine) (10 g, 45 mmol) and triethylamine (4.6 g, 45 mmol) in DCM (150 mL) was added solution of (Boc)20 (5.0 g, 23 mmol) in DCM (100 mL) cooled in an ice-bath and was stirred at rt overnight. The solution was concentrated to dryness and purified by flash column chromatography to give the title compound (5.976 g, 82.00% yield) as a slight yellow oil. MS (ESI): mass calcd. for ci5H32N2O5, 320.42; m/z found, 321.2 [M+H]+. |
72.2% | With sodium chloride; In tetrahydrofuran; methanol; | Part C Preparation of N-(3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)(tert-butoxy)formamide A 1 L 3-neck round bottom flask was fitted with a 500 mL addition funnel with nitrogen line, a thermometer, and a mechanical stirrer. The flask was charged with <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> (72.5 g, 0.329 mol), anhydrous THF (250 mL), and anhydrous MeOH (100 mL). The addition funnel was charged with a solution of di-tert-butyl dicarbonate (22.4 g, 0.103 mol) in anhydrous THF (100 mL). The contents of the addition funnel were added to the flask with rapid stirring at ambient temperatures over 30 min, causing a slight rise in temperature from 21 C. to 32 C. The reaction was stirred an additional 3 h at ambient temperatures and the solvents were removed under reduced pressure. The resulting thick syrup was taken up in sat. NaCl (1500 mL) and extracted with ether (5*1000 mL). The combined ether extracts were dried (MgSO4) and concentrated to give a colorless oil (29.8 g). A 5.00 g sample of this oil was purified by flash chromatography on silica gel (DCM:MeOH:TEA, 20:15:0.75) to give the title compound as a colorless oil (4.00 g, 72.2%). 1H NMR (CDCl3): 5.13 (s, 1H), 3.63-3.47 (m, 12H), 3.17 (q, J=6.2 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H), 1.75-1.64 (m, 4H), 1.39 (s, 9H), 1.36 (s, 2H); MS: m/e 321.2 [M+H]. |
72.2% | With sodium chloride; In tetrahydrofuran; methanol; | Part C Preparation of N-(3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)(tert-butoxy)formamide A 1 L 3-neck round bottom flask was fitted with a 500 mL addition funnel with nitrogen line, a thermometer, and a mechanical stirrer. The flask was charged with <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> (72.5 g, 0.329 mol), anhydrous THF (250 mL), and anhydrous MeOH (100 mL). The addition funnel was charged with a solution of di-tert-butyl dicarbonate (22.4 g, 0.103 mol) in anhydrous THF (100 mL). The contents of the addition funnel were added to the flask with rapid stirring at ambient temperatures over 30 min, causing a slight rise in temperature from 21 C. to 32 C. The reaction was stirred an additional 3 h at ambient temperatures and the solvents were removed under reduced pressure. The resulting thick syrup was taken up in sat. NaCl (1500 mL) and extracted with ether (5*1000 mL). The combined ether extracts were dried (MgSO4) and concentrated to give a colorless oil (29.8 g). A 5.00 g sample of this oil was purified by flash chromatography on silica gel (DCM:MeOH:TEA, 20:15:0.75) to give the title compound as a colorless oil (4.00 g, 72.2%). 1H NMR (CDCl3): 5.13 (s, 1H), 3.63-3.47 (m, 12H), 3.17 (q, J=6.2 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H), 1.75-1.64 (m, 4H), 1.39 (s, 9H), 1.36 (s, 2H); MS: m/e 321.2 [M+H] |
72.2% | With sodium chloride; In tetrahydrofuran; methanol; | Part C Preparation of N-(3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)(tert-butoxy)formamide A 1 L 3-neck round bottom flask was fitted with a 500 mL addition funnel with nitrogen line, a thermometer, and a mechanical stirrer. The flask was charged with <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> (72.5 g, 0.329 mol), anhydrous THF (250 mL), and anhydrous MeOH (100 mL). The addition funnel was charged with a solution of di-tert-butyl dicarbonate (22.4 g, 0.103 mol) in anhydrous THF (100 mL). The contents of the addition funnel were added to the flask with rapid stirring at ambient temperatures over 30 min, causing a slight rise in temperature from 21 C. to 32 C. The reaction was stirred an additional 3 h at ambient temperatures and the solvents were removed under reduced pressure. The resulting thick syrup was taken up in sat. NaCl (1500 mL) and extracted with ether (5*1000 mL). The combined ether extracts were dried (MgSO4) and concentrated to give a colorless oil (29.8 g). A 5.00 g sample of this oil was purified by flash chromatography on silica gel (DCM:MeOH:TEA, 20:15:0.75) to give the title compound as a colorless oil (4.00 g, 72.2%). 1H NMR (CDCl3): 5.13 (s, 1H), 3.63-3.47 (m, 12H), 3.17 (q, J=6.2 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H), 1.75-1.64 (m, 4H), 1.39 (s, 9H), 1.36 (s, 2H); MS: m/e 321.2 [M+H]. |
71.98% | In dichloromethane; at 0 - 25℃; for 18h; | Bis- ( 3-aminopropyl ) diethyleneglycol (98 g, 97.5 mL, 0.44 mol) was dissolved in DCM (1960 mL, 20 vol.) and Boc-anhydride (38.84 g, 0.177 mol) in DCM (980 mL, 10 vol.) was added dropwise within 4h at 0C. The mixture was left to react overnight at room temperature. The reaction was completed according to TLC, the reaction mixture was evaporated to ~0.5 L, the residue was washed four times with saturated NaCl solution (500 mL each) to remove excess diamine. The organic layer was quenched with 10% w. KHSO4 to pH ~4. The organic phase was separated to remove doubly protected diamine and the aqueous phase was basified with 6N NaOH to pH ~10, extracted with DCM (3*250 mL) , organic layer was successively washed with water and brine. The organic phase was dried (MgSOi) and concentrated in vacuo to yield the title compound (41 g, 71.9 percent yield) as a colorless oil. TLC control (SiC>2, CHCI3 : MeOH : 25%w NH3 in H2O = 8:2:0.2) : Rf = 0.6, ninhydrin stain. NMR confirmed the structure & purity . NMR (400 MHz, Chloroform-d) d 5.12 (s, 1H) , 3.68 - 3.49 (m, 12H), 3.23 (q, J = 6.3 Hz, 2H) , 2.82 (t, J = 6.7 Hz, 2H) , 1.76 (q, J = 6.6 Hz, 4H) , 1.45 (s, 9H) . |
49% | In chloroform; at 20℃; for 12h; | A solution of <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> (7.5g, 34.1mmol) in CHCl3 (100mL) was treated with BOC-anhydride (3.7g, 16.9mL). The mixture was stirred at room temperature for 12h. The solvent was removed, and the resulting yellow oil was purified by silica gel flash chromatography to produce the oil 5.5g of tert-butyl (3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)carbamate (4), Yield: 49%. 1H NMR (CDCl3, 400MHz): delta 5.1 (s, 1H), 3.58-3.50 (m, 12H), 3.21 (d, J=6.9Hz, 2H), 2.79 (t, J=8Hz, 2H), 1.75-1.69 (m, 4H), 1.59 (s, 2H), 1.42 (s, 9H). 13C NMR (CDCl3, 100MHz): delta 155.0, 69.2, 68.9, 66.7, 48.0, 37.6, 30.4, 28.6, 27.3. |
49% | In 1,4-dioxane; at 20℃; for 12h; | A solution of <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> (7.5 g, 34.1 mmol) in 1,4-dioxane(100 mL) was treated with BOC-anhydride (3.7 g, 16.9 mL). The mixture was stuffedat room temperature for 12 h. The solvent was removed, and the resulting yellow oilwas purified by silica gel flash chromatography to produce the oil 5.5 g of tert-butyl(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)carbamate, Yield: 49 %. 1H NMR(CDC13, 400 MHz): oe 5.1 (s, 1H), 3.58-3.50 (m, 12H), 3.21 (d, J= 6.9 Hz, 2H), 2.79 (t,J= 8Hz, 2H), 1.75-1.69 (m, 4H), 1.59 (s, 2H), 1.42 (s, 9H). 13C NMR (CDC13, 100MHz): oe 155.0, 69.2, 68.9, 66.7, 48.0, 37.6, 30.4, 28.6, 27.3. |
16% | With triethylamine; In chloroform; at 0℃; for 0.666667h; | Preparation of compound 69: To a solution of 4,7, 10-trioxa-l, 13-tridecanediamine (2.2 g, 10 mmol) in CHC13 (100 mL) at 0 C was added Boc20 (2.18 g, 10 mmol) and Et3N (1.4 mL, 10 mmol). The reaction was stirred at 0 C for 40 min. The reaction was concentrated to give crude product. The crude product was purified by column chromatography using 2-6% EtOH in CH2C12 to give purified product as slight yellow oil (516 mg, 16%). Note: the mono- protected amine must be freshly prepared. It undergoes gradual disproportionation upon storage. Analytical data matched that described in /. Am. Chem. Soc. 2003, 125, 2416- 2425. |
In tetrahydrofuran; acetonitrile; | Step 9A Synthesis of N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)(tert-butoxy)formamide A solution of at least three equivalents of <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> in tetrahydrofuran is cooled to 0 C., and a solution of one equivalent of di-tert-butyl dicarbonate in acetonitrile is added dropwise with stirring. The solution is stirred under nitrogen overnight and then concentrated. The residue is dissolved in ether and washed with five portions of saturated sodium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated to an oil, which is purified by flash chromatography to afford the monoamine. | |
In dichloromethane; at 0 - 20℃; for 2h; | 2 g (9.1 mmol) 4,7,10-trioxatridecane-1,13-diamine were dissolved in 15 ml DCM and 1 g (4.6 mmol) di-tert.-butyl-dicarbonate in 10 ml DCM was added dropwise at 0 C. The solution was stirred for 2 h at room temperature and the organic phase was washed five times with water. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to approximately 10 ml. Mono-boc-4,7,10-trioxatridecane-1,13-diamine was precipitated as hydrochloride salt by the addition of 2 M HCl in diethyl ether (yield: 1.1 g, 3.1 mmol, 67%). | |
50 g of the diamine (4,7,10-Trioxa-1,13-Tridecanediamine) was dissolved in 250 ml of dichlormethane. 17.5 mL of trifluoroacetic acid was added dropwise to the clear colorless solution. 49.5 g of di-tertbutyl-dicarbonate in 2000 ml of dichlormethane was added dropwise over 5 hours to the solution. The reaction mixture was stirred over night at room temperature and then concentrated in vacuum, yielding of clear yellow oil.The oil was dissolved in dichlormethane and the desired compound was extracted into 2×0.1N HCl (250 ml).The water phase was treated with 280 ml 1 N NaOH. The basic water phase was extraced twice with 250 ml of dichlormethane. The combined organic phases were washed with brine (200 ml). The dichloromethane was evaporated in vacuum yielding a clear light yellow oil. | ||
In chloroform; at 20℃; for 12.5h; | Reaction Step 1:; Preparation of N-Boc-4,7,10-trioxatridecane-13-amine To a solution of 151.40 g (687.25 mmol) of 4,7,10-trioxa-1,13-tridecaneamine in 700 mL CHCl3 was added 6.00 g (27.5 mmol) of di-tert-butyl dicarbonate in 100 mL CHCl3 with stirring at ambient temperature over 30 minutes. The mixture was stirred for 12 hours, washed with water (8×100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield 8.23 g (25.7 mmol) of the desired product as a clear oil: 1H NMR (CDCl3, delta): 5.18 (s, 1H, CONH), 3.55 (m, 12H -OCH2), 3.20 (m, 2H CH2NHCO), 2.68 (t, 2H CH2NH2), 1.73 (m, 4H), 1.41 (s, 9H). | |
In dichloromethane; at 20℃; | Synthesis of compound 14 (0061) Compound 13 (10 g, 45.5 mmol) was dissolved in 500 ml DCM, at room temperature, (Boc)2O (9.4 g, 43.18 mmol) was dissolved in 100 ml DCM, add drops into reaction solution, react overnight; add 200 ml water into reaction solution, adjust pH value to 3-4, extract the organic phase to remove the impurities, adjust the pH value of water phase to 10, then add saturated sodium chloride solution, extract the product, wash the organic phase with saturated sodium chloride solution (10 ml x6) to remove the unfinished raw materials, dry with sodium sulfate, evaporate the solvent, to give the colorless oil-like product(compound 14: 4.7 g, 34.1 % yield). (0062) 1H NMR (400 MHz, CDCl3): delta 5.11 (br s, 1 H), 3.63-3.45 (m, 12 H), 3.21 (t, J = 6.0 Hz, 2 H), 2.81 (t, J = 6.4 Hz, 2 H), 1.77-1.42 (m, 6 H), 1.42 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In N,N-dimethyl-formamide for 1h; Inert atmosphere; | 21.2 Step 2: To a solution of 4,7,10-trioxododecanel,13-diamine (6.7 g, 30.4 mmol) in anhydrous DMF(100 mL) was drop-wise added a solution of 2 (2.0 g, 5.86 mmol) in dry DMF (50 mL) over a period of 30 min under N2. The resulting thick white suspension was stirred for 30 min. The precipitate was filtered and washed with DMF. The combined filtrate was concentrated and diethyl ester was added. The precipitate (sticky solid) was collected and purified by flash chromatography (DCM/ MeOH = 5/1) to give desired compound 3 (2.44 g, yield 93%, M+H+ =448.5) |
67% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 72h; | |
61.5% | In N,N-dimethyl-formamide at 0℃; for 2h; | Synthesis of 3 Biotin succinimidylester (500 mg, 1.5 mmol) in 5 mL DMF was added dropwise by syringe to a solution of Diethylene Glycol Bis(3-aminopropyl) Ether (0.98 mL, 4.5 mmol) in 5 mL DMF at 0. After addition, the reaction mixture was stirred at 0 for 2h. The mixture was concentrated and the crude product was purified by silica gel column chromatography (CH2Cl2: MeOH = 50:1) to get the product 3 as colorless oil 412 mg, 61.5%. 1H NMR (400 MHz, CDCl3) δ 4.55-4.48 (m, 1H), 4.34-4.31 (m, 1H), 3.64-3.55 (m, 25H), 3.33-3.32 (m, 2H), 3.15-3.14 (m, 1H), 2.89-2.72 (m, 6H), 2.23-2.20 (m, 2H), 1.79-1.72 (m, 10H), 1.46-1.42 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 173.32, 163.98, 70.55, 70.49, 70.35, 70.13, 69.99, 69.83, 69.60, 69.46, 61.93, 60.11, 55.82, 40.62, 39.54, 37.26, 35.78, 32.75, 28.87, 28.04, 25.65. HRMS(ESI): m/z [M+H+] calculated for C20H35N4O5S: 447.2641, found: 447.2640. |
15 mg | In dimethyl sulfoxide at 20℃; for 0.25h; | 1 Synthesis of Biotin-PEG3-NH2 Synthesis of Biotin-PEG3-NH2 (2) Biotin (1, 13.5 mg, 55.3 pmol, 1 eq) was dissolved in 100 pL of dimethylsulfoxide (DMSO) and diisopropylethylamine (DIEA) was added (19.3 jtL, 2 eq). O-(N-succinimidyl)-N,N,N’,N’-tetramethyl-uronium (TSTU, 15.0 mg, 0.9 eq) was added and the clear solution was stirred for 10 minutes at room temperature to form the biotin-NHS estet 4,7,10-Trioxa-1,13-tride- canediamine (18 mg, 1.5 eq) was dissolved in 200 pL of dry DMSO and the biotin-NHS was added drop wise under vigorous stirring over 5 minutes. The mixture was stirred for a thrther 10 minutes at room temperature. 1.5 mL of diethyl ether was added to the clear solution and the resulting suspension was centrifuged. The supernatant ether phase was discarded and the remaining oil was purified by preparative RP-HPLC (5 mL/min, 10-100% acetonitrile in 0.1% TFA in H20). The fractions containing the product were lyophilized to afford 2 as a yellowish liquid (15mg, 67%). [HRMS (ESI):447.42 mlz (447.7 mlz expected). ‘H NMR (400 MHz, DMSO) ö 7.78 (t, 1H, J=5.6 Hz), 7.70 (m, 2H), 6.42 (d, 1H, J=0.2 Hz), 6.37 (m, 1H), 4.31 (m, 1H), 4.13 (dd, 1H, J=7.6, 4.5 Hz), 3.50 (m, 1 1H), 3.39 (t, 2H, J=6.3 Hz), 3.08 (m, 3H),2.85 (m, 3H), 2.05 (t, 2H, J=7.4 Hz), 1.78 (m, 2H), 1.61 (m, 4H), 1.49 (m, 3H), 1.30 (m, 2H). ‘3C NMR (101 MHz, DMSO) ö 172.4, 163.2, 70.2, 70.1, 70.0, 70.0, 68.6, 67.8, 61.5, 59.7, 55.9, 40.3,37.3,36.2,35.7,29.9,28.7,28.5,27.7, 25.8.] |
Yield | Reaction Conditions | Operation in experiment |
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71 mg | Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
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47 mg | Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
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20% | Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
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34% | Stage #1: biotin With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: 4,7,10-trioxa-1,13-diaminotridecane In N,N-dimethyl-formamide for 3h; Inert atmosphere; | |
Stage #1: 4,7,10-trioxa-1,13-diaminotridecane With 4-nitrophenol modified Wang resin; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 6h; Stage #2: biotin With N-ethylmorpholine;; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol In N,N-dimethyl-formamide for 12h; Stage #3: With triethylsilane; trifluoroacetic acid for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | In dichloromethane at 20℃; for 18h; | 8 4,7,10-trioxa-1,13-tridecanediamine-diglycolicylate (13) Dissolve 187 mL 7,7,10-trioxa-1,13-tridecanediamine (852 mmol) in 1000 mL dichloromethane. Add 33 g (284 mmol) diglycolic anhydride and allow to react 18 hours overnight at room temperature. Evaporate in vacuo to a thick syrup. Take up in 350 mL dichloromethane and triturate with 1050 mL diethyl ether. Repeat two times. Flash chromatography with silica gel using methanol/dichloromethane/triethylamine (25:70:5), and incrementally increasing methanol content to 30%, yielded 39 g (40%) of desire product 13 after evaporation. |
In acetonitrile at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In methanol at 120℃; for 5h; | 2.1; 2.2; 2.3 In a one-liter batch reactor a heel was formed by adding 254 grams of methanol, 8.5 grams of Grace 2724 sponge cobalt catalyst to a reactor. The reactor was pressure cycled three times with nitrogen, three-times with hydrogen, and then, heated to 120 °C. To this reactor was incrementally added 310 grams of nitrile feed in four hours. 254 grams of methanol and 8.5 grams of Grace 2724 cobalt catalyst. The reactor was pressure cycled three times with nitrogen, three-times with hydrogen, and then, heated to 120 °C. To this reactor was incrementally added 423 grams of nitrile feed in five hours. The nitrile feed was made by reacting DEG (LiOH present at 1000 ppm) with acrylonitrile at a molar ratio of 1:2.03 such that the concentration of dicyanoethyl DEG and monocyanoethyl DEG in the reaction product was about 9:1. Once the hydrogenation was over the product was removed using a filter, and then, the subsequent runs were started using the same catalyst with fresh solvent and feed. The subsequent hydrogenation reactions were carried out at 800 psig (56 bar) and 120 °C. The results are shown in the Table. | |
With hydrogen In DMF (N,N-dimethyl-formamide) at 120℃; for 5h; | 4.1; 4.2; 4.3; 4.4; 4.5; 4.6; 4.7; 4.8; 4.9 In a one-liter batch reactor a heel was formed by adding 120 grams of dimethylformamide (DMF), 7.2 grams of Grace 2724 sponge cobalt catalyst. The reactor was pressure cycled three times with nitrogen and three times with hydrogen. The contents were heated to 120°C. To this reactor was incrementally added 360 grams of nitrile feed in four hours. The nitrile feed was made by reacting DEG (LiOH present at 1000ppm) with acrylonitrile at a molar ratio of 1:2.03 such that the concentration of dicyanoethyl DEG and monocyanoethyl DEG was about 9:1 in the product. Once the hydrogenation was over the product was removed using a filter, and then, the subsequent runs were started using the same catalyst with fresh solvent and feed. The subsequent hydrogenation reactions were carried out at 800 psig (56 bar) and 120°C. The results are shown in the Table. | |
With hydrogen In tert-butyl methyl ether at 120℃; for 5h; | 5.1 In a one-liter batch reactor a heel was formed by adding 120 grams of methyl-tertiary-butylether (MTBE), 7.2 grams of Grace 2724 sponge cobalt catalyst. The reactor was pressure cycled three times with nitrogen and three times with hydrogen. The contents were heated to 120°C. To this reactor was incrementally added 360 grams of nitrile feed in five hours. The nitrile feed was made by reacting DEG (LiOH present at 1000 ppm) with acrylonitrile at a molar ratio of 1:2.03 such that the concentration of dicyanoethyl DEG and monocyanoethyl DEG was about 9:1 in the product. Once the hydrogenation was over the product was removed using a filter, and then, the subsequent runs were started using the same catalyst with fresh solvent and feed. The subsequent hydrogenation reactions were carried out at 800 psig (56 bar) and 120°C. The results are shown in the Table. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In tert-butyl methyl ether at 120℃; for 5h; | 5.2; 5.3; 5.4 In a one-liter batch reactor a heel was formed by adding 120 grams of methyl-tertiary-butylether (MTBE), 7.2 grams of Grace 2724 sponge cobalt catalyst. The reactor was pressure cycled three times with nitrogen and three times with hydrogen. The contents were heated to 120°C. To this reactor was incrementally added 360 grams of nitrile feed in five hours. The nitrile feed was made by reacting DEG (LiOH present at 1000 ppm) with acrylonitrile at a molar ratio of 1:2.03 such that the concentration of dicyanoethyl DEG and monocyanoethyl DEG was about 9:1 in the product. Once the hydrogenation was over the product was removed using a filter, and then, the subsequent runs were started using the same catalyst with fresh solvent and feed. The subsequent hydrogenation reactions were carried out at 800 psig (56 bar) and 120°C. The results are shown in the Table. | |
With hydrogen In tetrahydrofuran at 120℃; for 5h; | 6.2; 6.3 In a one-liter batch reactor a heel was formed by adding 120 grams of tetrahydrofuran (THF), 7.3 grams of Grace 2724 sponge cobalt catalyst. The reactor was pressure cycled three times with nitrogen and three times with hydrogen. The contents were heated to 120°C. To this reactor was incrementally added 360 grams of nitrile feed in four hours. The nitrile feed was made by reacting DEG (LiOH present at 1000 ppm) with acrylonitrile at a molar ratio of 1:2.03 such that the concentration of dicyanoethyl DEG and monocyanoethyl DEG was about 9:1 in the product. Once the hydrogenation was over the product was removed using a filter, and then, the subsequent runs were started using the same catalyst with fresh solvent and feed. The subsequent hydrogenation reactions were carried out at 800 psig (bar) and 120°C. The results are shown in the Table. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | In dichloromethane; at 0℃; for 3.5h; | [0093] As depicted in Scheme 3, a solution of benzylchloroformate (1.3 mL, 9 mmol) in DCM (20 mL) was added over 1.5 h to a solution of compound 8 (2 gr, 9 mmol) and triethyl amine (3.8 ml, 27 mmol) in DCM (40 mL) cooled at 0C. The solution was stirred for 2 h at 0C, then warmed to room temperature. After completion the crude was concentrated by evaporation and the product was purified by column chromatography (Hex:EtOAc) to give product 9 (1.3 gr, 40% yield). ?H NMR (400 MHz, CDC13) 7.21- 7.11 (m, 5H), 4.89 (s, 2H), 3.46-3.3 1 (m, 12H), 3.07 (dd, I = 12.6, 6.3 Hz, 2H), 2.94 (t, I =6.5 Hz, 2H), 1.84-1.76 (m, 1H), 1.64-1.56 (m, 1H). ?3C NMR (101 MHz, CDC13) 157.58,137.35, 129.06, 128.58, 128.47, 70.78, 70.54, 70.40, 69.63, 66.97, 50.32, 39.36, 39.16,30.06, 27.39. MS (ESI+) mlz: 255. |
With triethanolamine; In tetrahydrofuran; methanol; | Part A-Preparation of N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)(phenylmethoxy)formamide A solution of <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> (158 mL, 0.72 mol), TEA (16.7 mL, 0.12 mol), and MeOH (300 mL) in peroxide-free THF (1,000 mL) was placed in a 3 liter 3-neck flask fitted with a mechanical stirrer, a thermometer, and an addition funnel with nitrogen line. The addition funnel was charged with a solution of benzyl chloroformate (17.1 mL, 0.12 mol) in peroxide-free THF (1,000 mL). The contents of the flask were cooled below 5 C. The contents of the addition funnel were added to the flask with rapid stirring over 4 h while keeping the temperature below 5 C. The solution was stirred an additional 30 min and concentrated to give a thick syrup. This syrup was taken up in saturated NaCl (1800 mL) and 10% Na2CO3 (200 mL) and extracted with ether (3*1,000 mL). The combined ether extracts were washed with saturated NaCl (500 mL), dried (MgSO4), and concentrated to give a pale yellow oil (36.74 g). Flash chromatography on a 7*29 cm silica gel column (DCM/MeOH/TEA, 20/15/0.5) gave the title compound as a colorless syrup (19.14 g, 45%). 1H NMR (CDCl3): 7.33-7.25 (m, 5H), 5.59 (s, 1H), 5.06 (s, 2H), 3.62-3.45 (m, 12H), 3.32-3.25 (m, 2H), 2.74 (t, J=6.7 Hz, 2H), 1.75 (pentet, J=6.0 Hz, 2H), 1.67 (pentet, J=6.4 Hz, 2H), 1.33 (s, 2H); MS: m/e 355.4 [M+H]; High Resolution MS: Calcd for C18H31N2O5 [M+H]: 355.2233, Found: 355.2222. | |
With triethanolamine; In tetrahydrofuran; methanol; | Part A-Preparation of N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)(phenylmethoxy)formamide A solution of <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> (158 mL, 0.72 mol), TEA (16.7 mL, 0.12 mol), and MeOH (300 mL) in peroxide-free THF (1,000 mL) was placed in a 3 liter 3-neck flask fitted with a mechanical stirrer, a thermometer, and an addition funnel with nitrogen line. The addition funnel was charged with a solution of benzyl chloroformate (17.1 mL, 0.12 mol) in peroxide-free THF (1,000 mL). The contents of the flask were cooled below 5 C. The contents of the addition funnel were added to the flask with rapid stirring over 4 h while keeping the temperature below 5 C. The solution was stirred an additional 30 min and concentrated to give a thick syrup. This syrup was taken up in saturated NaCl (1800 mL) and 10% Na2CO3 (200 mL) and extracted with ether (3*1,000 mL). The combined ether extracts were washed with saturated NaCl (500 mL), dried (MgSO4), and concentrated to give a pale yellow oil (36.74 g). Flash chromatography on a 7*29 cm silica gel column (DCM/MeOH/TEA, 20/15/0.5) gave the title compound as a colorless syrup (19.14 g, 45%). 1H NMR (CDCl3): 7.33-7.25 (m, 5H), 5.59 (s, 1H), 5.06 (s, 2H), 3.62-3.45 (m, 12H), 3.32-3.25 (m, 2H), 2.74 (t, J=6.7 Hz, 2H), 1.75 (pentet, J=6.0 Hz, 2H), 1.67 (pentet, J 6.4 Hz, 2H), 1.33 (s, 2H); MS: m/e 355.4 [M+H]; High Resolution MS: Calcd for C18H31N2O5 [M+H]: 355.2233, Found: 355.2222. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.5h; | EXAMPLE 2; Method for Preparation of a Water-soluble Biotinylation Reagent This Example sets forth a general methodology for preparing a biotin moiety linked to a water-soluble linker moiety. In the example, a diamino-ether linker is used. Ether linkers containing terminal functionalities such as, an amine and a carboxylate; an amine and an alcohol; an alcohol and a carboxylate; and two alcohols, can also be prepared using the method described. The general method can also be used when the linker contains polyhydroxyl groups if the terminal functionalities are two amines, or are an amine and a carboxylate. Preparation of A Biotin Compound Containing A Trioxo-Amide Linker With An Amine Terminus The TFP ester of biotin (5 g, 12.8 mmol) (Example 1) was dissolved in 200 mL anhydrous DMF. In another flask containing 28 g (128 mmol) <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> was added 4 mL of triethylamine. Both the flasks were cooled to 0-5 C. by ice water. The TFP ester of biotin was added, dropwise, to the trioxatridecanediamine solution over the period of 1 hour. The mixture was stirred at room temperature for 30 minutes and the solvent was removed under vacuum. The resulting oil was triturated in 500 mL ether and was stirred for 30 minutes. The solid was filtered. The solid product was dissolved in methanol:ethyl acetate (8:2) and loaded on silica column. The column was eluted with methanol:ethyl acetate (8:2). Fractions containing product were collected and the solvent was removed under vacuum. The isolated product was dried under vacuum to yield 4.5 g (79%) of desired product as a colorless solid, mp=104-106 C. 1H NMR (MeOH, delta): 1.46 (m, 2H), 1.6-1.8 (m, 9H), 2.2 (t, 2H), 2.7 (d, 1H), 2.75-2.9 (m, 3H), 3.2-3.3 (m, 5H), 3.5-3.6 (m, 14H); 4.3 (m, 1H), 4.5 (m, 1H), 1R (KBr, cm-1) 3280, 2910, 2850, 1690, 1640, 1110, 940.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; Cooling with ice; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate; In toluene; at 100℃; for 48h;Inert atmosphere; | To a stirred solution of 500 mg (2065 mmol) 1-chloro-9,10-anthraquinone and 1 g 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propan-1-amine) (4.544 mmol) in 40 ml of toluene was added 1480 g of cesium carbonate (4544 mmol). The reaction mixture was stirred at 100 C for 48 h until the reaction was completed. The solvent was evaporated and filtered. The residue was dissolved in dichloromethane (250 ml) and washed with water (2 x 100). The organic phase was dried over sodium sulfate and evaporated. The crude was finally purified by flash chromatography mixture of dichloromethane and methanol (90:10) obtaining of 572 mg desired compound with yield 65%. TLC (SiO2): CH2Cl2: MeOH (5:0.2); Rf = 0.20. MALDI - TOF MS: m/z 427.4 [M+H]+; (MW = 426.5). IR (neat) (cm-1): 3070, 2927, 1666, 1630, 1593, 1510, 1271,1069, 870, 806, 736. 1H NMR (CDCl3): delta (ppm): 1.97-2.03 (p, 4H, N-CH2-CH2-CH2-O, J1 = J2 = J3 = J4 = 6.4 Hz); 3.41-3.72 (m, 18H, N-CH2-CH2-CH2-O, O-CH2-CH2-O); 7.05-7.07 (dd, 1H, H2-Ar, J1 = 1.6 HzJ1 = 8.4 Hz); 7.47-7.49 (d, 1H, H4-Ar, J1 = 7.2 Hz,); 7.50-7.55 (dt,2H, H3-Ar, H6-Ar, J1 = 1.2 Hz, J1 = 1.6 Hz, J2 = 6.6 Hz, J2 = 7.4 Hz,J3 = 7.0 Hz); 7.64-7.68 (dt, 2H, H3-Ar, H6-Ar, J1 = 1.2 Hz,J2 = 7.6 Hz, J2 = 7.2 Hz, J3 = 7.4 Hz); 8.17-8.19 (dd, 1H, H5-Ar,J1 = 1.2 Hz, J1 = 1.6 Hz, J2 = 7.8 Hz);8.21-8.24 (dd, 1H, H7-Ar, J1 = 1.6 Hz, J2 = 7.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | 3-Diphenylphosphino-4-hydroxy-benzoic acid (Example 1d, 100 mg, 0.31 mmol) and PyBOP (177 mg, 3.41 mmol) are dissolved in 5 ml DMF/CH3CN (1:1) and stirred for 5 min at room temperature. <strong>[4246-51-9]4,7,10-Trioxa-1,13-tridecanediamine</strong> (136 mg, 6.2 mmol) and triethylamine (46 Dl) are added and the reaction mixture stirred at room temperature for 48 h. All volatiles are removed in vacuo and the residue purified by flash column chromatography (CH2CI2/MeOH 95:5) to yield 142 mg (0.27 mmol, 87%) of the title compound as a colorless wax. ESI-MS 525.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With diisopropyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 24h; | In an argon atmosphere 0.50 g (1.31 mol, 1.00 eq) of <strong>[2389-60-8]Z-Lys(Boc)-OH</strong>), 32.0 mg (0.26 mmol, 0.20 eq) of 4-dimethylaminopyridine (DMAP), 250 mg (307 mu, 1.97 mmol, 1.5 eq) of diisopropylcarbodiimide (DIC) and 72 mg (72 mu^, 0.33 mmol, 0.25 eq) of 4,7,10-trioxa-l, 13-tridecandiamine were dissolved in dry dichloromethane (15 mL) and the solution was stirred at room temperature for 24 h. After filtration of the precipitated urea, dichloromethane was evaporated and the remaining residue was purified over silica gel column, eluting with dichloromethane/methanol (30: 1) to yield the product as a colorless oil. Yield 250 mg (0.26 mmol, 79%).-NMR (300 MHz, CDC13): delta [ppm] = 1.31-1.49 (m, 13H, CH3, CH2), 1.59- 1.85 (m, 4H, CH2), 3.07 (brs, 2H, CH2), 3.26-3.40 (m, 2H, CH2), 3.52-3.61 (m, 6H, CH2), 4.1 1-4.16 (m, 1H, CH), 4.74 (brs, 1H, NH), 5.08 (s, 2H, CH2), 5.77 (brs, 1H, NH), 6.89 (brs, 1H, NH), 7.28-7.34 (m, 5H, CH-arom). Rf: 0.07 in dichloromethan/methanol 30: 1. HRMS (ESI): m/z calcd for C48H77N6Oi3: 945.5612; found: 945.5612; calcd for C48H76N6NaOi3 : 967.5363; found: 967.5431. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In chloroform at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: ethanol / 20 h / Reflux 2: N,N-dimethyl-formamide / 16 h / 20 °C 3: hydrogenchloride / methanol; water / 16 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: 1,4-dioxane / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 0.17 h / Schlenk technique; Cooling with ice 2.2: 48 h / 20 °C / Cooling with ice; Schlenk technique 3.1: trifluoroacetic acid / dichloromethane / Inert atmosphere; Cooling with ice | ||
Multi-step reaction with 3 steps 1.1: (benzotriazole-1-yl-oxy)-tris-(pyrrolidinophosphonium) hexafluorophosphate / tetrahydrofuran / 1 h / -65 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; (benzotriazole-1-yl-oxy)-tris-(pyrrolidinophosphonium) hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / Inert atmosphere 2.2: 24 h / 20 °C / Inert atmosphere 3.1: potassium carbonate / methanol; water / 16 h / 20 °C / Inert atmosphere |
Multi-step reaction with 3 steps 1.1: tetrahydrofuran 2.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol; triethylamine / N,N-dimethyl-formamide / 0.5 h / 40 °C / Inert atmosphere 2.2: Inert atmosphere 3.1: hydrogenchloride / methanol | ||
Multi-step reaction with 3 steps 1: triethylamine / chloroform / 0.67 h / 0 °C 2: triethylamine; dmap / dichloromethane / 1 h / 20 °C 3: hydrogenchloride; water / dichloromethane / 0.5 h / 0 °C | ||
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 20 °C / Cooling with ice 2.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere 2.2: 16 h / Inert atmosphere 3.1: hydrogenchloride / methanol / 50 °C | ||
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 12 h / 20 °C 2: dicyclohexyl-carbodiimide; dmap / dichloromethane / 24 h / 20 °C 3: trifluoroacetic acid / dichloromethane / 3 h / -5 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 2,4,6-trimethyl-pyridine; benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl-formamide; at 0℃; for 2h; | HOBt (73 mg, 0.54 mmol), HBTU (204.8 mg, 0.54 mmol) and Sym-collidine (118.9 mL, 0.90 mmol) were sequentially added to a stirred solution of commercially available 15b (50 mg, 0.227 mmol) and N-Boc-(S)-2-Phenylglycine (142 mg, 0.567 mmol) in dry DMF (2 mL) at 0 C. The reaction mixture was left stirring for 2 hours and then, after reaction completion, the mixture was diluted with EtOAc (20 mL) and washed with a saturated solution of ammonium chloride (3 x 20 mL), saturated solution of sodium bicarbonate (3 x 20 mL) and brine (1 x 20 mlL. The organic layers were dried over Na2SO4, and then the solvent was removed under reduced pressure. The residue was purified by BiotageTM flash chromatography, eluant conditions: from 1% of MeOH and 99% of CH2Cl2 to 10% of MeOH and 90% of CH2Cl2. Yield 94 % (146 mg, MW 686.85, 0.212 mmol) of pure 16b. Analytical characterization: 1H-NMR (400 MHz, CDCl3): d: 7.39-7.28 (m, 10H), 6.55 (bs, 2H), 5.94 (bs, 2H), 5.10 (bs, 2H), 3.59-3.31 (m, 16H), 1.70 (t, J = 6.0 Hz, 4H), 1.42 (s, 18H); 13C-NMR (100 MHz, CDCl3): d: 170.3, 138.9, 128.8, 128.1, 127.2, 79.8, 70.4, 70.1, 69.7, 38.1, 28.7, 28.3. ESI-MS: m/z 687.6 [M+H]+, 709.5 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example 2: (1 ff,8S,9ff)-Bicyclo[6.1.0]non-4-yn-9-ylmethyl (4,7,10-trioxa-13-azatridecyl) carbamate (exo-14) To a solution of exo-13 (400 mg, 1 .27 mmol) in DMF (20 mL) was added 4,7, 10- trioxa-1 , 13-tridecanediamine (1.67 mL, 7.61 mmol) followed by Et3N (531 mu, 3.81 mmol). The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure, the residue was dissolved in CH2CI2 (40 mL) and extracted with 1 N NaOH (2 x 10 mL), followed by water. The combined aqueous layers were extracted with EtOAc (3 x 10 mL) and washed with brine. The combined organic layers were dried over MgS04 and concentrated in vacuo to give a yellow oil. Purification by column chromatography (hexanes: EtOAC, 5: 1 - MeOH + 1 % Et3N, visualised with l2) yielded exo-14 as a slightly yellow oil (0.435 mg, 1 .10 mmol, 86%). 1 H NMR (500 MHz; CDCI3) delta 5.39 (1 H, brs), 3.96 (2 H, d, J 6.6), 3.65-3.63 (4 H, m), 3.61 -3.54 (8 H, m), 3.28 (2 H, d, J 6.0), 2.81 (2 H, t, J 6.6), 2.41 -2.38 (2 H, m), 2.31 - 2.25 (2 H, m), 2.17-2.12 (2 H, m), 1.79-1.74 (4 H, m), 1 .40-1 .33 (2 H, m), 0.72-0.66 (3 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 22h;Inert atmosphere; | General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example 5: (1 ff,8S,9S)-Bicyclo[6.1.0]non-4-yn-9-ylmethyl 4,7,10-trioxa-13-4.7.10-trioxa-13- aminotridecylcarbamate (endo-14) To a solution of endo-13 (150 mg, 0.48 mmol) in DMF (10 mL) was added 4,7, 10- trioxa-1 , 13-tridecanediamine (0.625 mL, 2.85 mmol) followed by Et3N (200 mu, 1 .43 mmol). The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure, the residue was dissolved in CH2CI2 (20 mL) and extracted with 1 N NaOH (2 x 10 mL), followed by water. The combined aqueous layers were extracted with EtOAc (3 x 10 mL) and washed with brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give a yellow oil. Purification by column chromatography (hexanes: EtOAC, 5: 1 - MeOH + 1 % Et3N, visualised with l2) yielded endo-14 as a slightly yellow oil (0.172 mg, 0.43 mmol, 90%). 1 H NMR (500 MHz; CDCI3) 1H NMR (500 MHz; CDCI3) delta 5.39 (1 H, brs), 4.13 (2 H, d, J 8.2), 3.64-3.59 (12 H, m), 3.28 (2 H, d, J 5.9), 2.88 (2 H, t, J 6.3), 2.36-2.19 (6 H, m), 1 .80-1.75 (4 H, m), 1.62-1 .56 (2 H, m), 1 .37-1 .33 (1 H, m), 0.95-0.91 (2 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Example 3Preparation of Diol 3 Derived from Tyrosine ([Fmoc-Tyr]2-PEG)10184] A solution of Fmoc-Tyr(tl3u)-OH (0.5 g, 1.09 mmol), WSC.HC1 (0.4 g, 2.12 mmol) andHOl3t (0.29 g, 2.19 mmol) in DMF (3 mE) in a 10 mE round-bottom flask was stirred at room temperature for 10 mm. Then, 4,7, 10-trioxa- 1,13-tridecanediamine (0.12 ml, 0,547 mmol) was added dropwise during 15 mm. The reaction mixture was stirred for 15 mm at room temperature. The solvent was removed by rotatory evaporation. The crude was solved in 35 ml DCM and washed with 4x50 ml of water. The organic layer was dried over Na2SO4, filtered and the solvent removed by rotaevaporation to afford the product (a white solid, 97%). Depro14tection of tert-butyl protecting groups was carried out by solving the product obtained before in 10 ml TFA:DCM 1:1 and stirring the solution for 30 mm. at room temperature. Then, the solvent was evaporated under N2 and the resulting crude was suspended in a low volume of 0.2 M HC1:ACN 1:1 and lyophilized (96%). Mw 991.1 g/mol. ?H-NMR (400 MHz, dmso-d6): 1.56 (4H, m), 2.66 (1H, dd), 2.80 (1H, dd), 3.31 (2H, t), 3.43 (16H, m), 4.07 (2H, m), 4.12 (4H, d), 4.18 (2H, s), 4.21 (1H, m), 6.61 (4H, d), 7.03 (4H, d), 7.29 (4H, d), 7.39 (4H, t), 7.65 (4H, t), 7.87 (4H, d), 9.07 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With caesium carbonate; In acetonitrile; at 100℃; for 120h;Inert atmosphere; | To a solution of 270 mg (0.407 mmol) 1,8-bis((2-(4-methylbenzenesulfonyloxy)ethyl)(methyl)amino)anthracene-9,10-dione and 197 mg 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propan-1-amine) (0.896 mmol) in 50 ml of acetonitryle was added 291 mg of cesium carbonate (0.83 mmol). The reaction mixture was stirred at 100 C for 5 day under inert gas. The reaction mixture was cooled to room temperature, filtered and the solvent was removed under reduced pressure. The red residue was purified by flash column chromatography using silica gel and dichloromethane as eluent to give 214 mg of desired compound with yield 62%. TLC (SiO2): CH2Cl2; Rf = 0.22. 1H NMR (CDCl3): delta (ppm): 1.74-1.95 (p, 4H, N-CH2-CH2-CH2-O); 3.88 (s, 3H, CH3-N-); 3.95 (s, 3H, CH3-N-); 3.20-3.78 (m,44H, CH3-N-CH2-CH2-N, N-CH2-CH2-CH2-O, O-CH2-CH2-O);7.19-7.21 (d, 1H, H2-Ar, J1 = 7.6 Hz); 7.30-7.32 (d, 1H, H4-Ar,J1 = 7.2 Hz,); 7.40-7.44 (t, 2H, H3-Ar, H6-Ar, J1 = 8.4 Hz,J1 = 4.8 Hz, J2 = 6.6 Hz); 7.60-7.63 (d, 1H, H5-Ar, J1 = 8.4 Hz);7.79-7.81 (d, 1H, H7-Ar, J1 = 7.6 Hz). MALDI - TOF MS: m/z 760.0 [M+H]+; 798.3[M+K]+;(MW = 759.0). IR (neat) (cm-1): 3270, 2924, 2857, 1870, 1663, 1583, 1091,747. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With caesium carbonate; In toluene; at 80℃; for 168h;Inert atmosphere; | To a solution of 500 mg <strong>[82-43-9]1,8-dichloro-9,10-anthraquinone</strong> (1.8 mmol) 994 mg 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propan-1-amine) (4.51 mmol) in 50 ml of toluene was added 1469 g of cesium carbonate (4.51 mmol). The reaction mixture was stirred at 80 C for 7 days. After completion of the reaction (TLC monitoring) the reaction mixture was filtered and solvent was removed under reduced pressure. The crude product was purified by flash column chromatography using silica gel and mixture of dichloromethane and methanol (99:1) as eluent to give 320 mg red solid with yield 50%. TLC (SiO2): CH2Cl2: MeOH (5:0.5); Rf = 0.35. 1H NMR (CDCl3): delta (ppm): 1.95-2.03 (p, 8H, N-CH2-CH2-CH2-O,); 3.43-3.78 (m, 32H, N-CH2-CH2-CH2-O, O-CH2-CH2-O);7.11-7.13 (d, 1H, H2-Ar, J1 = 7.6 Hz); 7.44-7.49 (t, 2H, H3-Ar, H6-Ar, J1 = 8.4 Hz, J1 = 7.6 Hz, J2 = 8.0 Hz); 7.69-7.71 (d, 1H, H4-Ar,J1 = 6.8 Hz,); 7.75-7.77 (d, 1H, H5-Ar, J1 = 7.6 Hz); 8.13-8.15 (d,1H, H7-Ar, J1 = 8.0 Hz). MALDI - TOF MS: m/z 645.7 [M+H]+; 668.6 [M+Na]+; (MW = 644.8). IR (neat) (cm-1): 2867, 1665, 1615, 1514, 1117, 748. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | General procedure: To a solution of N-Boc protected l-proline (3.00 g, 13.9 mmol) in anhydrous CH2Cl2 (40 mL) was added Et3N (2.0 mL, 14.6 mmol) and the mixture was cooled to 0C. Then, ethyl chloroformate (1.40mL, 14.6mmol) was added dropwise over 15min. The reaction temperature was maintained at 0C for 30 min, followed by dropwise addition of a solution of o-phenylenediamine (0.320g, 7.84mmol) in CH2Cl2 (10mL) over 15min. The resulting reaction mixture was then stirred for 30min at ambient temperature and then diluted with CH2Cl2 (20mL), followed by addition of H2O (10mL). Then, the organic layer was extracted with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was further purified using column chromatography eluting with 50% ethyl acetate/petroleum ether. The product was obtained as white solid (2.90g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 46% 2: 17% | With copper(l) iodide; 2-(3-methylbutyryl)cyclohexanone; caesium carbonate In N,N-dimethyl-formamide at 140℃; Inert atmosphere; | Catalytic arylation of polyamines General procedure: A two-necked flask equipped with a magnetic stirrer was flushed with dry argon and charged with aryl halide (1.25 mmol), CuI (9.5 mg, 10 mol%), ligand L1(11.5 mg, 20 mol%) or L2 (17 mg, 20 mol%), solvent (1 ml), appropriate amine (0.5 mmol) and Cs2CO3 (1.25 mmol, 420 mg). The reaction mixture was stirred under reflux (EtCN, MeCN) or at 140 °C (DMF)for 24-30 h. After cooling to room temperature, the mixture was dilutedwith CH2Cl2 (5 ml), the solid was filtered off, the filtrate was evaporated in vacuo, and the residue was analyzed by 1H NMR spectroscopy. To obtain individual compounds, the residue was chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (50:1-3:1),CH2Cl2-MeOH-aq. NH3 (100:20:1-10:4:1). Target compounds were obtained as yellow or brown viscous oils or solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In N,N-dimethyl-formamide; at 0℃; for 0.5h; | To a finely ground mixture of <strong>[68528-80-3]suberic acid bis(N-hydroxysuccinimide ester)</strong> (37 mg, 0.1 mmol) in DMF (1.5 ml) at 0, 5.5 mul of O,O-(dipropylamine diethyleneglycol) was added by dropwise and stirred for 30 min and fractionated by RP-HPLC to give product 1 (10.3 mg, 57% yield), using initial isocratic eluting with acetonitrile: TFA (v/v = 250:1) in water, followed by gradient eluting from acetonitrile: TFA (v/v = 250:1) in water to acetonitrile (100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With copper; In water; at 100℃; for 1h; | Synthesis an analog of derivative 6-ABT-1 where theDNP moiety is substituted by pyrimidine expected andlater shown experimentally to have no affinity for antiSO3H DNP antibodies was initiated by coupling of 2-bromopyrimidine to the diamine 3,3 -((oxybis(ethane-2, 1 -diyl))bis(oxy))bis(propan- 1-amine) using Hartwig-Buchwald Pd(O) coupling conditions however this was unsuccessful likely due to deactivating chelation of the amine ligand to palladium. Alternative Ullman-type conditions were employed by dissolving the diamine (100mg, 0.45mmol) and 2-bromo-pyrimidine (57mg, 0.36mmol) in 2ml del water open to atmosphere followed by the addition of copper metal (1.4mg, 0.O23mmol). Upon heating for 1 hr at 100C the solution turned a bluish-green and the reaction was quenched using 1 M HCL. The solution was concentrated and purified by ISCO Cl 8 chromatography to yield the pyrimidine-monoamine linker intermediate X in 80% yield as a slightly yellowish oil (86mg ,0.29mmol) ?H NMR (500 Mhz, DMSO-d6) 8.42 (s, 2H), 8.24 (d, J 4.7 Hz, 2H), 7.08 (t, J 5.4 Hz, 111), 6.53 (t, J= 4.7 Hz, 111), 3.54-3.42 (m, 10H), 3.29 (q, J= 6.6 Hz, 4H), 2.77 (t, J 7.2 Hz, 2H), 1.73 (dp, J= 13.7, 6.5 Hz, 4H). IIRMS (ES+) calc?d for C14H,7N40, (M+H) 299.2005. Found299.2011. Intermediate X (86mg ,0.29mmol) was coupled to Boc-L-nipecotic acid and deprotecteddescribed above for linker ABT- 1 to yield ABT-4 in quantitative yield (118mg, 0.29mmol) and used directly in the next step. The di-bromo intermediate Viii (8mg, 0.Ol4mmol) was coupled to linker ABT-4 (11 .4mg,0.O28mmol) and purified exactly as described above for 6-ABT-1 resulting in the isolation of 6-ABT-4 in 43% yield (5.2mg,0.Oo6mmol) ?H NMR (500 Mhz, DMSO-d6) 11.70 (s,111), 8.43 (d, J= 8.1 Hz, 1H), 8.26 (d, J= 4.6 Hz, 2H), 8.14 (d, J= 12.6 Hz, 2H), 7.86 (t, J 5.4 Hz, 111), 7.81 (t, J 7.5 Hz, 111), 7.69 (t, J= 7.6 Hz, 1H), 7.62 (d, J 9.9 Hz, 1H), 7.55 (d, J? 8.2 Hz, 111), 7.07 (brs, 111) 6.55 (t, J 4.8 Hz, 111), 6.37 (s, 111), 4.62 (brs, 211), 4.18 (brs, 2H), 3.51-3.35 (m,1OH), 3.26 (m, 4H), 3.16-3.04 (m, 2H), 1.92-1.78 (m, 1H), 1.71 (t,J= 10.0 Hz, 4H), 1.65 (m, 4H).13C NMR (151 MHz, DMSO) 175.30, 172.60, 163.47, 158.09, 154.26, 152.01, 148.65, 145.47,144.63, 139.97, 135.67, 133.67, 131.75, 128.92, 128.28, 126.95, 126.26, 124.12, 123.77, 122.16,119.46, 110.11, 97.17, 96.80, 70.17, 69.94, 68.64, 68.42, 52.22, 49.16, 42.70, 38.49, 36.16, 29.66,29.42, 28.00, 24.17. IIRMS (ES+) calc?d for C40H46N7012S2 (M+H) 880.2568m/z. Found 880.2538. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13%; 76% | With potassium carbonate; In dichloromethane; at 20℃; for 4h; | K2CO3 (1.0mmol) and 4,7,10-trioxatridecane-1,13-diamine (VIII, 0.175mmol) were added to four solutions of compounds 13, 14, 15, or 16 (0.35mmol of each) in DCM (20mL each). Each reaction mixture was stirred at rt for 4h and then diluted with water and extracted three times with DCM. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Finally, each residue was purified by column chromatography, using hexane/ethyl acetate as solvents and thus the dimeric compounds 17 (76%), 18 (81%), 19 (79%), or 20 (85%) were yielded, respectively. Small percentages of the monomeric compounds (9, 13%; 10, 10%; 11, 11%; or 12, 7%) were also yielded, respectively. 4.10.1 Compound 17 White solid, mp 139-141C; [alpha]25D+26 (c 1 in MeOH); IR numax(KBr)/cm-1 3672, 2922, 2863, 2844, 1628, 1054, 1033, 1012 and 839; deltaH (CD3OD, 400MHz): 7.28 (dd, 1H, J1=J2=5.2Hz, NH PEG group), 5.42 (dd, 1H, J1=J2=3.2Hz, H-12), 3.74-3.18 (m, 16H, CH2O PEG group), 3.22 (dd, 1H, J1=J2=6.8Hz, H-3), 2.83 (dd, 1H, J1=3.6, J2=13.2Hz, H-18), 1.24, 1.04, 1.01, 1.01, 0.97, 0.85, 0.84 (s, 3H each, methyl groups); deltaC (CD3OD, 100MHz) see TableS3 (Supplementary material); ESI-HRMS m/z calcd for C70H117N2O7 [M+1]+ 1097.8861, found 1097.8876. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10%; 81% | With potassium carbonate; In dichloromethane; at 20℃; for 4h; | K2CO3 (1.0mmol) and 4,7,10-trioxatridecane-1,13-diamine (VIII, 0.175mmol) were added to four solutions of compounds 13, 14, 15, or 16 (0.35mmol of each) in DCM (20mL each). Each reaction mixture was stirred at rt for 4h and then diluted with water and extracted three times with DCM. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Finally, each residue was purified by column chromatography, using hexane/ethyl acetate as solvents and thus the dimeric compounds 17 (76%), 18 (81%), 19 (79%), or 20 (85%) were yielded, respectively. Small percentages of the monomeric compounds (9, 13%; 10, 10%; 11, 11%; or 12, 7%) were also yielded, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11%; 79% | With potassium carbonate; In dichloromethane; at 20℃; for 4h; | K2CO3 (1.0mmol) and 4,7,10-trioxatridecane-1,13-diamine (VIII, 0.175mmol) were added to four solutions of compounds 13, 14, 15, or 16 (0.35mmol of each) in DCM (20mL each). Each reaction mixture was stirred at rt for 4h and then diluted with water and extracted three times with DCM. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Finally, each residue was purified by column chromatography, using hexane/ethyl acetate as solvents and thus the dimeric compounds 17 (76%), 18 (81%), 19 (79%), or 20 (85%) were yielded, respectively. Small percentages of the monomeric compounds (9, 13%; 10, 10%; 11, 11%; or 12, 7%) were also yielded, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7%; 85% | With potassium carbonate; In dichloromethane; at 20℃; for 4h; | K2CO3 (1.0mmol) and 4,7,10-trioxatridecane-1,13-diamine (VIII, 0.175mmol) were added to four solutions of compounds 13, 14, 15, or 16 (0.35mmol of each) in DCM (20mL each). Each reaction mixture was stirred at rt for 4h and then diluted with water and extracted three times with DCM. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Finally, each residue was purified by column chromatography, using hexane/ethyl acetate as solvents and thus the dimeric compounds 17 (76%), 18 (81%), 19 (79%), or 20 (85%) were yielded, respectively. Small percentages of the monomeric compounds (9, 13%; 10, 10%; 11, 11%; or 12, 7%) were also yielded, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With sodium hydrogencarbonate; In tetrahydrofuran; for 5.33333h;Cooling with ice; | [Synthesis of Polymerizing Compound M-1] (0268) 40.0 g (182 mmol) of <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong>, 37.8 g (450 mmol) of sodium hydrogen carbonate, 100 g of water, and 200 g of tetrahydrofuran were added to a 1 L three neck flask including a stirrer, and 35.2 g (389 mmol) of acrylic acid chloride was added dropwise to the mixture over 20 minutes in an ice bath. The solution after the dropwise addition was stirred at room temperature for five hours, and then tetrahydrofuran was distilled away from the obtained reaction mixture at reduced pressure. Next, a water layer was extracted four times using 200 ml of ethyl acetate, the obtained organic layer was dried using magnesium sulfate, and then was filtered, and a solvent was distilled away at reduced pressure, thereby obtaining 35.0 g (107 mmol, yield 59%) of target solid Polymerizing Compound M-1. |
59% | With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 5.3h;Cooling with ice; | 40.0 g (182 mmol) of <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong>, 37.8 g (450 mmol) of sodium hydrogencarbonate, 100 g of water and 200 g of tetrahydrofuran were added to a 1 L three-necked flask equipped with a stirrer , 35.2 g (389 mmol) of acrylic acid chloride was added dropwise over 20 minutes in an ice bath. After the dropwise addition, the mixture was stirred at room temperature for 5 hours, and tetrahydrofuran was distilled off from the obtained reaction mixture under reduced pressure. Next, the aqueous layer was extracted four times with 200 ml of ethyl acetate, and the obtained organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a solid of the objective polymerizable compound M-2 (107 mmol, yield 59%) |
59% | With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 5.3h;Cooling with ice; | In a 1 L three-necked flask equipped with a stirrer, 40.0 g (182 mmol) of <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong>,37.8 g (450 mmol) of sodium bicarbonate,100 g of water and 200 g of tetrahydrofuran were added,Under an ice bath,35.2 g (389 mmol) of acrylic acid chloride was added dropwise over 20 minutes.After the dropwise addition, the mixture was stirred at room temperature for 5 hours,From the resulting reaction mixture, tetrahydrofuran was distilled off under reduced pressure.Next, the aqueous layer was extracted four times with 200 ml of ethyl acetate,The obtained organic layer was dried with magnesium sulfate,Filtration was carried out,The solvent was distilled off under reduced pressure to obtain a solid of the objective polymerizable compound M-135.0 g (107 mmol, yield 59%) was obtained. |
35.1% | With 4-methoxy-phenol; triethylamine; In dichloromethane; at 2 - 20℃; for 26h; | A 1 L four-necked flask was charged with diethylene glycol bis(3-aminopropyl) ether (Tokyo Chemical Industry Co., 33.0 g, 0.15 mol), triethylamine (30.4 g, 0.30 mol), p-methoxyphenol (3.7 mg, 0.03 mmol), dichloromethane Were charged, stirred, and cooled to an internal temperature of 2 C. 100 mL of dichloromethane solution of acrylic acid chloride (27.2 g, 0.30 mol) was added dropwise at 5 C. or lower over 2 hours. After the dropwise addition, the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered, insoluble matter was washed with dichloromethane, and concentrated under reduced pressure at 35 C. or less. The concentrated residue thus obtained was purified using silica gel column chromatography (developing solvent: ethyl acetate: methanol = 4: 1). After purification of the column, a white solid was obtained by distilling off the solvent under reduced pressure by a rotary evaporator. It performs LC / MS analysis and IH-NMR measurement, the position and the integral value of the signal, a white solid obtained was confirmed to be the compound of interest. The yield was 17.3 g, and the yield was 35.1%. |
35.1% | With 4-methoxy-phenol; triethylamine; In dichloromethane; at 2 - 20℃; for 26h; | In a 1 L four-necked flask, diethylene glycol bis (3-aminopropyl) ether (manufactured by Tokyo Chemical Industry Co., Ltd., 33.0 g, 0.15 mol)Triethylamine (30.4 g, 0.30 mol), p-methoxyphenol (3.7 mg, 0.03 mmol) and dichloromethane 250 mL were charged, stirred and cooled to an internal temperature of 2 C.100 mL of dichloromethane solution of acrylic acid chloride (27.2 g, 0.30 mol) was added dropwise at 5 C. or lower over 2 hours.After the dropwise addition, the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered, insoluble matter was washed with dichloromethane, and concentrated under reduced pressure at 35 C. or less. The concentrated residue thus obtained was purified using silica gel column chromatography (developing solvent: ethyl acetate: methanol = 4: 1). After purification of the column, a white solid was obtained by distilling off the solvent under reduced pressure using a rotary evaporator. LC / MS analysis and 1 H-NMR measurement were performed, and it was confirmed from the position and integral value of the signal that the obtained white solid was a target compound. The yield was 17.3 g, and the yield was 35.1%. |
35.1% | With 4-methoxy-phenol; triethylamine; In dichloromethane; at 2 - 20℃; for 24h; | Diethylene glycol bis(3-aminopropyl)ether (manufactured by Tokyo Chemical Industry Co., Ltd.; 33.0 g, 0.15 mol), triethylamine (30.4 g, 0.30 mol), p-methoxyphenol (3.7 mg, 0.03 mmol), and 250 mL of dichloromethane were put into a 1-liter four-neck flask, stirred, and cooled to an internal temperature of 2 C. One-hundred milliliters of a dichloromethane solution of acrylic acid chloride (27.2 g, 0.30 mol) was then added dropwise over the course of 2 hours at 5 C. or lower. After the dropwise addition of the solution, the resulting mixture was stirred for 24 hours under room temperature conditions. The reaction solution was filtered, and insoluble matters were washed with dichloromethane. The filtrate was concentrated under reduced pressure at 35 C. or lower. The concentrated residue thus obtained was purified by silica gel column chromatography (developing solvent: a 4:1 mixture of ethyl acetate and methanol). After the column purification, the solvent was removed under reduced pressure using a rotary evaporator, and a white solid was obtained. The solid was subjected to LC/MS analysis and 1H-NMR measurement. It was determined from the locations and integrals of signals that the white solid was a target compound. The weight yield was 17.3 g, and the percentage yield was 35.1%. MS m/z: 329 (M+H)+ 1H-NMR (270 MHz D2O): delta 1.70 (tt, 4H), 3.25 (t, 4H), 3.46-3.60 (m, 12H), 5.62 (m, 2H), 6.10 (m, 2H), 6.15 (m, 2H) (ppm) |
33% | With triethylamine; In dichloromethane; at 20℃; for 2h;Cooling with ice; | Into a 1 L three-necked flask equipped with a stirrer, 22.0 g (0.1 mol) of polyfunctional amine (A-7)24.3 g (1.2 equivalents) of triethylamine,500 ml of methylene chloride was added, and under ice bath,19.9 g (1.1 equivalent) of acrylic acid chloride,Was added dropwise over 1 hour,Thereafter, the mixture was stirred at room temperature for 1 hour. After disappearance of the raw material was confirmed by 1 H-NMR, And the salt precipitated in the reaction solution was removed by filtration.The obtained filtrate was washed with 400 ml of 1N hydrochloric acid water,10% sodium chloride water 400 ml,1 N sodium bicarbonate water 400 ml,10% sodium chloride water 400 ml in this order,20 g of magnesium sulfate was added,After filtration, the solvent was distilled off under reduced pressure with heating at 40 C.Thereafter, 50 ml of acetonitrile was added, heated to dissolve, slowly cooled to room temperature to confirm crystal precipitation, and 50 ml of ethyl acetate was slowly added while cooling with ice. The precipitated crystals were collected by filtration,And dried under reduced pressure to obtain 10.8 g of polyfunctional acrylamide compound AA-7.The yield was 33%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium methylate; In methanol; at 40℃; for 7h; | In a 1 L three-necked flask equipped with a stirrer, 307 g of methyl beta-diethylaminopropionate, 7.7 g of 28% sodium methoxide methanol solution was added,While maintaining the liquid temperature at 40 C. in a water bath, 211.5 g (0.96 mol) of polyfunctional amine (A-7)Was added dropwise to the reaction solution over 1 hour.Subsequently, the mixture was reacted at 40 C. for 6 hours,The reaction solution was subjected to NMR measurement to confirm that A-7 disappeared,The reaction was terminated. 1.9 g of concentrated sulfuric acid was added to the reaction solution to neutralize it,The precipitated salt was filtered off and heated under reduced pressure to remove low boiling point substances, yielding 446 g of polyfunctional aminoamide compound (AM-7) (yield 98%).The structure of AM-7 obtained was identified by NMR and MS |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | Stage #1: (R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoic acid With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In tetrahydrofuran at 22℃; Stage #2: 4,7,10-trioxa-1,13-diaminotridecane In dichloromethane at 22℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Peptapeptide 1 (44 mg, 0.050 mmol, 1.0 eq), HOBt (10 mg, 0.075 mmol, 1.5 eq), HBTU (38 mg,0.10 mmol, 2.0 eq), and DIPEA (41 L, 0.25 mmol, 5.0 eq) were dissolved in 500 L of DMF, andthen <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> (220 L, 1.0 mmol, 20 eq) was added. The mixture wasstirred overnight at r.t. The reaction mixture was precipitated with diethyl ether, and the solid wasdissolved in dichloromethane. The organic layer was washed with water and dried over Na2SO4.After concentration, the mixture was purified by column chromatography (silica gel:CH2Cl2-MeOH,10:1) to produce amino-modified cyclic pentapeptide 2 as a light yellow solid in an 81% yield (44 mg,0.041 mmol). ESI-HRMS: m/z = 1101.5633, calcd for C52H81N10O14S m/z = 1101.5654 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: 4,7,10-trioxa-1,13-diaminotridecane With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Stage #2: N-(fluoren-9-ylmethoxycarbonyl)glycine 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; N,N-dimethyl-formamide Stage #3: Fmoc-Pro-OH; 1-hexadecylcarboxylic acid Further stages; | AA15 Molecule AA15 is obtained by the conventional method of solid phase peptide synthesis (SPPS) on 2-chlorotrityl resin. DIPEA (8.64 mL, 49.60 mmol) is added to a solution of 4,7,10-trioxa-1,13-tridecanediamine (TOTA, 10.87 mL, 49.60 mmol) in DCM (50 mL). This solution is then poured onto 2-chlorotrityl resin (4.00 g, 1.24 mmol/g) previously washed with DCM in a reactor adapted to SPPS. After stirring for 2 hours at room temperature, methanol (0.8 ml/g, 3.2 ml) is added and the medium is stirred for 15 minutes. The resin is filtered, washed successively with DCM (350 ml), DMF (250 ml), DCM (250 ml), isopropanol (150 ml) and DCM (350 ml). Protected amino acids N-Fmoc-L-glycine and N-Fmoc-L-proline, then palmitic acid (3 equivalents) are coupled successively using 1-[bis (dimethylamino) methylene]-1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU, 3 equivalents) as coupling agent in the presence of DIPEA (6 equivalents) in a 1:1 DCM/DMF mixture. A solution of 20% piperidine in DMF is used for the cleavage steps of the Fmoc protecting group. The resin is washed with DCM, DMF and isopropanol after each coupling and deprotection step. Cleavage of the resin product is carried out using a 1:1 TFA/DCM mixture. The solvents are evaporated under reduced pressure, the residue is solubilized in DCM (50 mL) and the organic phase is washed with a 1N aqueous solution of NaOH (150 mL), then a saturated solution of NaCl (250 mL). After drying over Na2SO4, the organic phase is filtered, concentrated under reduced pressure and the residue is purified by chromatography on silica gel (dichloromethane, methanol, NH4OH). Yield: 1.65 g (54% overall over 7 steps).1H-NMR (CDCl3, ppm): 0.88 (3H); 1.18-2.39 (38H); 2.79 (2H); 3.23-3.44 (2H); 3.47-3.69 (14H); 3.76 (0.92H); 3.82 (0.08H); 3.98 (0.08H); 4.03 (0.92H); 4.34 (0.08H); 4.39 (0.92H); 7.00-7.40 (2H). LC/MS (ESI): 613.7; (calculated ([M+H]+): 613.5). |
54% | Stage #1: 4,7,10-trioxa-1,13-diaminotridecane With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Stage #2: N-(fluoren-9-ylmethoxycarbonyl)glycine 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; N,N-dimethyl-formamide Stage #3: Fmoc-Pro-OH; 1-hexadecylcarboxylic acid Further stages; | AA15 EXAMPLE AA14; Molecule AA14 resin AA14-1: Product obtained by the reaction between 4,7,10-trioxa-1,13-tridecanediamine and the 2-Cl-trityl chloride resin. (1174) DIPEA (8.64 mL, 49.60 mmol) is added at room temperature to a solution of4,7,10-trioxa-1,13-tridecanediamine (10.87 mL, 49.60 mmol) in dichloromethane (50 mL). (1175) This solution is poured on 2-Cl-trityl chloride resin previously washed with dichloromethane (100-200 mesh, 1% DVB, 1.24 mmol/g) (4.00 g, 4.96 mmol) in a peptide synthesis reactor on a solid support. After stirring for 2 hours at room temperature, HPLC grade methanol (0.8 mL/g resin, 3.2 mL) is added and the mixture is stirred at room temperature for 15 minutes. The resin is filtered, washed successively with dichloromethane (3×50 mL), DMF (2×50 mL), dichloromethane (2×50 mL), isopropanol (1×50 mL) and dichloromethane (3×50 mL). (1176) resin AA14-2: Product obtained by reaction between resin AA14-1 and Fmoc-glycine. (1177) DIPEA (5.18 mL, 29.76 mmol) is added to a suspension of Fmoc-glycine (4.42 g, 14.88 mmol) and 1-[bis (dimethylamino) methylene]-1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU, 5.66 g, 14.88 mmol) in 1:1 DMF/dichloromethane (60 mL). After complete solubilization, the solution obtained is poured onto the resin AA14-1. After stirring for 2 hours at room temperature, the resin is filtered, washed successively with DMF (3×60 mL), isopropanol (1×60 mL) and dichloromethane (3×60 mL). (1178) resin AA14-3: Product obtained by reaction between AA14-2 resin and an 80:20 DMF/piperidine mixture. AA14-2 resin is treated with an 80:20 DMF/piperidine mixture (50 mL). After stirring for 30 h at room temperature, the resin is filtered, washed successively with DMF (3×50 mL), isopropanol (1×50 mL) and dichloromethane (3×50 mL). (1179) resin AA14-4: Product obtained by reaction between resin AA14-3 and Fmoc-proline. (1180) By a process similar to that used for resin AA14-2 applied to resin AA14-3 and Fmoc-proline (5.02 g, 14.88 mmol) in DMF (50 mL), resin AA14-4 is obtained. (1181) resin AA14-5: Product obtained by reaction between resin AA14-4 and an 80:20 DMF/piperidine mixture. (1182) By a process similar to that used for AA14-3 resin applied to AA14-4 resin and a 80:20 DMF/piperidine mixture (50 mL), resin AA14-5 is obtained. (1183) resin AA14-6: Product obtained by reaction between resin AA14-5 and palmitic acid. (1184) By a process similar to that used in the preparation of AA14-4 resin applied to AA14-5 resin and palmitic acid (3.82 g, 14.88 mmol), resin AA14-6 is obtained. (1185) Molecule AA14 (1186) Resin AA14-6 is treated with a 1:1 TFA/dichloromethane mixture (50 mL). After stirring for 30 minutes at room temperature, the resin is filtered and washed with dichloromethane (3×50 mL). The solvents are evaporated under vacuum. Two co-evaporations are then borne out on the residue with dichloromethane (50 ml), then diisopropyl ether (50 ml). The residue is solubilized in dichloromethane (50 mL) and the organic phase is washed with an aqueous solution of 1N NaOH (1×50 mL), then a saturated solution of NaCl (2×50 mL). After drying on Na2SO4, the organic phase is filtered, concentrated in vacuum and the residue is purified by chromatography on silica gel (dichloromethane, methanol, NH4OH) (1187) Yield: 1.65 g (54% overall over 7 steps) (1188) NMR 1H (CDCl3, ppm): 0.88 (3H); 1.18-2.39 (38H); 2.79 (2H); 3.23-3.44 (2H); 3.47-3.69 (14H); 3.76 (0.92H); 3.82 (0.08H); 3.98 (0.08H); 4.03 (0.92H); 4.34 (0.08H); 4.39 (0.92H); 7.00-7.40 (2H). (1189) LC/MS (ESI): 613.7; (calculated ([M+H]+): 613.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: 4,7,10-trioxa-1,13-diaminotridecane With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1.5h; Stage #2: Fmoc-Leu-OH 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; N,N-dimethyl-formamide Stage #3: Fmoc-Pro-OH; n-tetradecanoic acid Further stages; | A17; A19 Molecule 41: Product obtained by solid phase peptide synthesis (SPPS) General procedure: Molecule 41 is obtained by means of the conventional solid phase peptide synthesis (SPPS) method on 2-chlorotrityl resin (1185) To a solution of 4,7,10-trioxa-1,13-tridecanediamine (TOTA, 76.73 mL, 350 mmol) in DCM (350 mL) is added DIPEA (60.96 mL, 350 mmol). This solution is then poured onto the 2-chlorotrityl resin (47.30 g, 0.74 mmol/g) previously washed with DCM in a reaction vessel suitable for SPPS. After 1.5 h of stirring at ambient temperature, methanol (26 mL) is added and the medium is stirred for 15 min. The resin is filtered, washed successively with DCM (3×350 mL), DMF (2×350 mL), DCM (2×350 mL), isopropanol (1×350 mL) and DCM (3×350 mL). The γ-methyl ester of N-Fmoc-L-glutamic acid (1.5 eq) followed by molecule 36 (1.5 eq) are coupled using the coupling agent 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 1.5 equivalents) and DIPEA (3 equivalents) in a 1:1 DCM/DMF mixture. A 1:1 DMF/morpholine mixture is used for the cleavage step of the Fmoc protecting group. The resin is washed with DCM, DMF and methanol after each coupling and deprotection step. The cleavage of the product from the resin is carried out using a 1:1 TFA/DCM mixture. The solvents are then evaporated under vacuum; the residue is solubilized in DCM (500 mL) and the organic phase is washed with a 5% Na2CO3 aqueous solution (500 mL). After drying on Na2SO4, the organic phase is filtered, concentrated under vacuum and a yellow oil of molecule 41 is obtained after drying at reduced pressure. (1186) Yield: 15.95 g (65%) (1187) 1H NMR (DMSO-d6, ppm): 0.85 (3H); 1.16-1.31 (24H); 1.38-1.68 (6H); 1.68-2.37 (12H); 2.58 (2H); 3.01-3.17 (2H); 3.31-3.55 (14H); 3.58 (3H); 4.09-4.18 (0.7H); 4.18-4.29 (1H); 4.36-4.43 (0.3H); 7.62 (0.7H); 7.86 (0.7H); 7.98 (0.3H); 8.23 (0.3H). (1188) LC/MS (ESI): 699.4 (calculated ([M+H]+): 699.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with Pd(dba)2 and BINAP ligand, corresponding to aryl halide (1-1.25 mmol) and 5 mL absolute dioxane. After stirring the mixture for several minutes, the appropriate oxadiamine (0.5 mmol) and tBuONa (1.5 mmol) were added. The reaction mixture was refluxed for 8 h, and its work up was essentially the same as described for Cu(I)-catalyzed arylation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5%; 5% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4%; 12%; 44% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12%; 9%; 9% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19%; 20% | General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with CuI and the ligand (2-isobutyrylcyclohexanone or rac-BINOL); 1.25 mmol of the appropriate aryl halide and dry DMF (1 mL) were added followed by the oxadiamine (0.5 mmol). The reaction mixture was stirred for several minutes, then Cs2CO3 (1.25 mmol) was added and the reaction mixture was stirred at 140 oC for 24 h to ensure the full completion of the process. Next, the reaction mixture was cooled to ambient temperature, a small amount of the solution was taken for 1H NMR investigation of its composition, dichloromethane (5-10 mL) was added, the residue filtered off washed with dichloromethane (5-10mL), and the combined organic fractions were evaporated in vacuo and chromatographed on silica gelusing a sequence of eluents: CH2Cl2, CH2Cl2-MeOH (200:1, 100:1, 50:1, 20:1, 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 2-bromo-1-fluoro-4-(trifluoromethyl)benzene With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0) In 1,4-dioxane Inert atmosphere; Stage #2: 4,7,10-trioxa-1,13-diaminotridecane With sodium t-butanolate In 1,4-dioxane for 8h; Reflux; | General method (B) for Pd(0)-catalyzed N,N'-diarylation of oxadiamines. General procedure: The reaction vessel was flushed with dry argon, equipped with a magnetic stirrer and reflux condenser, and charged with Pd(dba)2 and BINAP ligand, corresponding to aryl halide (1-1.25 mmol) and 5 mL absolute dioxane. After stirring the mixture for several minutes, the appropriate oxadiamine (0.5 mmol) and tBuONa (1.5 mmol) were added. The reaction mixture was refluxed for 8 h, and its work up was essentially the same as described for Cu(I)-catalyzed arylation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.2% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 10 - 25℃; for 23h;Inert atmosphere; | In a 500 mL four-necked flask purged with nitrogen, 15.0 g (68 mmol) of <strong>[4246-51-9]4,7,10-trioxa-1,13-tridecanediamine</strong> and 41.5 g of 1,8-diazabicyclo[5.4.0]-7-undecene. (273 mmol) and 190 mL of acetonitrile were charged,The obtained mixture was cooled to 10 C. or lower, 30.0 g (276 mmol) of chlorotrimethylsilane was added dropwise, and then the reaction mixture was stirred at 25 C. for 23 hours. The extraction operation with 50 mL of heptane was performed 5 times on the reaction mixture. The heptane layer was concentrated under reduced pressure, filtered under nitrogen, and29.5 g of silylamine compound D represented by the above formula was obtained (yield 85.2%). The results of 1H-NMR analysis are shown below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 4,7,10-trioxa-1,13-diaminotridecane In dichloromethane at 20℃; for 2h; Stage #2: (9-fluorenylmethoxycarbonyl)-L-histidine 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 Stage #3: Fmoc-Pro-OH; 1-hexadecylcarboxylic acid Further stages; | A3 Example A3: Molecule A3 Molecule A3 is obtained by the method of solid phase peptide synthesis (SPPS) on 2-chlorotrityl resin A solution of 4,7,10-trioxa-1,13-tridecanediamine (TOTA, 68 mL, 310 mmol) in DCM (140 mL) is poured onto 2-chlorotrityl resin (13.60 g, 1.14 mmol/g, 15.5 mmol) washed beforehand with DCM in a reactor suitable for SPPS. After 2 h stirring at room temperature, methanol (0.8 mL/g, 11 mL) is added and the medium is stirred for 15 min. The resin is filtered, washed successively with DCM, DMF, DCM, isopropanol and DCM. The protected amino acids N-Fmoc-L-Histine (3-Bom) (10.03 g, 20.2 mmol, 1.3 equivalents) and N-Fmoc-L-proline (6.80 g, 20.2 mmol, 1.3 equivalents) then palmitic acid (5.17 g, 20.2 mmol, 1.3 equivalents) are successively coupled using 1-[bis (dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU, 1.3 equivalents) as a coupling agent in the presence of DIPEA (2.6 equivalents) in DMF. A 20% solution of piperidine in DMF is used for the Fmoc protecting group cleavage steps. The resin is washed with DCM, DMF and methanol after each coupling and deprotection step. Cleavage of the product of the resin is carried out using a 1:1 TFA/DCM mixture. The solvents are then evaporated under reduced pressure; the residue is solubilized in DCM (500 mL) and the organic phase is washed with an aqueous solution of NaOH 1N (1×200 mL). After drying over Na2SO4, the organic phase is filtered, then concentrated under reduced pressure. The molecule A4 is obtained in the form of a yellow oil. Yield: 10 g (79%) 1H NMR (CDClhd 3, ppm): 0.88 (3H); 1.19-1.41 (24H); 1.51-2.29 (14H); 2.29 (2H); 3.06-3.18 (1H); 3.18-3.33 (3H); 3.38-3.46 (3H); 3.51-3.65 (11H); 4.43-4.54 (3H); 4.61-4.68 (1H); 5.34 (2H); 6.74-6.77 (1H); 6.86-6.95 (1H); 7.28-7.39 (6H); 7.45- 7.49 (1H). (0936) LC/MS (ESI): 813.6; (calculated ([M+H]+): 813.6). |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
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P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
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P230 | Keep wetted |
P231 | Handle under inert gas. |
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P234 | Keep only in original container. |
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P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
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P314 | Get medical advice/attention if you feel unwell. |
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P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
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P337 | If eye irritation persists: |
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P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
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P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
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P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
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P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
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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 |
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