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CAS No. : | 51644-96-3 | MDL No. : | MFCD00210020 |
Formula : | C10H22N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DPLOGSUBQDREOU-UHFFFAOYSA-N |
M.W : | 202.29 | Pubchem ID : | 4352 |
Synonyms : |
PROTAC Linker 23
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.9 |
Num. rotatable bonds : | 8 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 57.41 |
TPSA : | 64.35 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.78 cm/s |
Log Po/w (iLOGP) : | 2.51 |
Log Po/w (XLOGP3) : | 1.06 |
Log Po/w (WLOGP) : | 1.64 |
Log Po/w (MLOGP) : | 1.26 |
Log Po/w (SILICOS-IT) : | 0.97 |
Consensus Log Po/w : | 1.49 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.23 |
Solubility : | 11.8 mg/ml ; 0.0583 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.0 |
Solubility : | 2.01 mg/ml ; 0.00994 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.5 |
Solubility : | 0.637 mg/ml ; 0.00315 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.12 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 2735 |
Hazard Statements: | H314 | 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 |
---|---|---|
72% | at 20℃; for 4.5 h; Cooling with ice | General procedure: A solution of di-tert-butyl dicarbonate (22 g, 100 mmol) inMeOH (20 mL) was added over 30 min to a stirred solutionof 1,4-diaminobutane (25, 1.8 g, 20 mmol) in MeOH (160 mL)under ice-cooling. After stirring for 4 h at room temperature,the solvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography (CHCl3:MeOH: aq. NH3=10 : 1 : 0.1) to give the title compound (26)in 83percent yield. |
51% | at 0 - 20℃; for 12 h; | [113] To a solution of 1,5-diaminopentane (15) (1.14 ml, 9.79 mmol) in dichloromethane (100 ml) was added di-tert-butyl dicarbonate (1.12 ml, 4.90 mmol) at 0 0C, and the resulting solution was stirred at room temperature for 12 hours. After the reaction was completed, H2O was added to remove solid residue. The reaction mixture was basified with IN NaOH aqueous solution to pH 10-11 and extracted with dichloromethane three times. Then, the combined organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to <n="14"/>silica gel column chromatography (eluent: dichloromethane:methnol: ammonia water = 100:9:1) to give the target compound as a yellow liquid (1.00 g, 51 percent).[114] 1H-NMR (400 MHz, CDCl3) δ 4.57 (br, IH, -NH-), 3.11-3.09 (d, J = 6.2 Hz, 2H, - NH-CH2-), 2.71-2.67 (t, J = 6.9 Hz, -CH2-(Bn)2), 1.78 (br, 2H, -NH2), 1.51-1.44 (m, 4H, -NH-CH2-CH2-, -Cu2- CH2- N-(Bn)2), 1.42 (s, 9H, -O(CH3)3), 1.37-1.31 (m, 2H, -CH2-CH2-CH2-). |
20% | With hydrogenchloride; sodium hydroxide In water; <i>tert</i>-butyl alcohol | EXAMPLE 2 1,5-Diaminopentane (14.0 ml, 120 mmol) was dissolved in tert.-butanol (70 ml) and was treated dropwise over a period of 10 minutes with di-tert-butyl dicarbonate (9.2 ml, 40 mmol). After the addition had been completed, the reaction mixture was stirred at room temperature for 16.5 hours. The reaction mixture was then treated with 1N sodium hydroxide solution (aq) (90 ml), stirred for 1 hour and finally extracted with chloroform. The chloroform extracts were dried (MgSO4) and concentrated under vacuum. The residue was dissolved in water, made acidic (pH=2) by the dropwise addition of 3N hydrochloric acid at 0° and was washed with ether to remove the diprotected diamine. The aqueous portion was made basic (pH 10) with 5percent sodium carbonate solution and was extracted with ethyl acetate to give 1.6 g (20percent) of mono-Boc-1,5-diaminopentane. |
20% | With hydrogenchloride; sodium hydroxide In water; <i>tert</i>-butyl alcohol | EXAMPLE 9 Preparation of: STR13 1,5-Diaminopentane (14.0 ml, 120 mmol) was dissolved in tert.-butanol(70 ml) and was treated dropwise over a period of 10 min with di-tert-butyl dicarbonate (9.2 ml, 40 mmol). After the addition had been completed, the reaction mixture was stirred at room temperature for 16.5 hr. The reaction was then treated with lN sodium hydroxide solution (aq) (90 ml), stirred for 1 hr and finally extracted with chloroform. The chloroform extracts were dried (MgSo4) and concentrated under vacuum. The residue was dissolved in water, made acidic (pH=2) by the dropwise addition of 3N hydrochloric acid at 0° and was washed with ether to remove the diprotected diamine. The aqueous portion was made basic (pH 10) with 5percent sodium carbonate solution and was extracted with ethyl acetate to give 1.6 g (20percent) of mono-Boc 1,5-diaminopentane. The structure was confirmed by 'H NMR and CI-MS. To a solution of the heptapeptide prepared in Example 8 and mono-Boc-1,5-diaminopentane in dimethylformamide, dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate is added. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine In 1,4-dioxane; water at 20℃; for 12 h; Inert atmosphere | A solution of 2-(Boc-oxyimino)-2-phenylacetonitrile (226 mg, 0.92 mmol) in 1,4-dioxane (30 mL) was added via syringe pump (rate=8 mL/hr) to a stirred solution of 1,5 diaminopentane dihydrochloride (1 g, 5.52 mmol) and TEA (1 ml, 7.12 mmol) in 1:1 1,4-dioxane:water (40 mL) under inert atmosphere at room temperature. The reaction was stirred for 12 h and DCM (20 mL) was added to the reaction mixture. The organic phase was extracted and concentrated in vacuo. The yellow residue was dissolved in diethyl ether (15 mL) and 5percent HCl solution added. The acidic solution was washed with diethyl ether and then the pH of the aqueous layer adjusted to pH 14 with 2.5M NaOH solution. Ethyl acetate (20 mL) was added and the organic layer was washed with brine (2×50 mL), and dried (MgSO4). The solvents were evaporated in vacua to yield N-Boc-cadaverine as a yellow oil (100 mg, 55percent). HPLC/MS (Hydrophilic/TFA) Rt=6.17 min; ESI MS (+ve) m/z=203 [M+1H); calc. m/z for C10H22N2O2: 202.3 g/mol, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With hydrogenchloride; sodium hydroxide In water; <i>tert</i>-butyl alcohol | EXAMPLE 2 1,5-Diaminopentane (14.0 ml, 120 mmol) was dissolved in tert.-butanol (70 ml) and was treated dropwise over a period of 10 min with di-tert-butyl dicarbonate (9.2 ml, 40 mmol). After the addition had been completed, the reaction mixture was stirred at room temperature for 16.5 hr. The reaction was then treated with 1N sodium hydroxide solution (aq) (90 ml), stirred for 1 hr and finally extracted with chloroform. The chloroform extracts were dried (MgSO4) and concentrated under vacuum. The residue was dissolved in water, made acidic (pH=2) by the dropwise addition of 3N hydrochloric acid at 0° and was washed with ether to remove the diprotected diamine. The aqueous portion was made basic (pH 10) with 5percent sodium carbonate solution and was extracted with ethyl acetate to give 1.6 g (20percent) of mono-Boc 1,5-diaminopentane. The structure was confirmed by 'H NMR and CI-MS. To a solution of the D-Tyr2 -proline heptapeptide, prepared as described in Example 1, (29.7 mg, 0.0331 mmol) and mono-Boc-1,5-diaminopentane (20.2 mg, 0.0996 mmol) in dimethylformamide (400 μl), dicyclohexylcarbodiimide (10.3 mg, 0.05 mmol) and 1-hydroxybenzotriazole hydrate (6.7 mg, 0.05 mmol) were added. The reaction mixture was stirred at room temperature for 19 hours. The dimethylformamide was, then, removed under vacuum. The residue was treated with trifluoroacetic acid at 0° for 2 hours. After this time, the trifluoroacetic acid was removed under vacuum and the residue in 1percent acetic acid was passed over a BioRex 70 (H+) ion exchange column. The basic products were washed off the ion exchange column with pyridine buffer (H2 O/pyridine/HOAc, 66:30:4) and evaporated. Final purification by prep HPLC (5μ Ultrasphere ODS) gave 5.4 mg (17percent) of pure [1-(β-mercapto-β,β-cyclopentamethylenepropionic acid)-2-D-tyrosine-4-valine-8-(1,5-diaminopentane)-8-desarginine- 9-desglycinamide]-vasopressin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In methanol; at 20℃; for 4.5h;Cooling with ice; | General procedure: A solution of di-tert-butyl dicarbonate (22 g, 100 mmol) inMeOH (20 mL) was added over 30 min to a stirred solutionof 1,4-diaminobutane (25, 1.8 g, 20 mmol) in MeOH (160 mL)under ice-cooling. After stirring for 4 h at room temperature,the solvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography (CHCl3:MeOH: aq. NH3=10 : 1 : 0.1) to give the title compound (26)in 83% yield. |
51% | In dichloromethane; at 0 - 20℃; for 12h; | [113] To a solution of 1,5-diaminopentane (15) (1.14 ml, 9.79 mmol) in dichloromethane (100 ml) was added di-tert-butyl dicarbonate (1.12 ml, 4.90 mmol) at 0 0C, and the resulting solution was stirred at room temperature for 12 hours. After the reaction was completed, H2O was added to remove solid residue. The reaction mixture was basified with IN NaOH aqueous solution to pH 10-11 and extracted with dichloromethane three times. Then, the combined organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to <n="14"/>silica gel column chromatography (eluent: dichloromethane:methnol: ammonia water = 100:9:1) to give the target compound as a yellow liquid (1.00 g, 51 %).[114] 1H-NMR (400 MHz, CDCl3) delta 4.57 (br, IH, -NH-), 3.11-3.09 (d, J = 6.2 Hz, 2H, - NH-CH2-), 2.71-2.67 (t, J = 6.9 Hz, -CH2-(Bn)2), 1.78 (br, 2H, -NH2), 1.51-1.44 (m, 4H, -NH-CH2-CH2-, -Cu2- CH2- N-(Bn)2), 1.42 (s, 9H, -O(CH3)3), 1.37-1.31 (m, 2H, -CH2-CH2-CH2-). |
1.6 g (20%) | With hydrogenchloride; sodium hydroxide; In water; tert-butyl alcohol; | EXAMPLE 2 1,5-Diaminopentane (14.0 ml, 120 mmol) was dissolved in tert.-butanol (70 ml) and was treated dropwise over a period of 10 minutes with di-tert-butyl dicarbonate (9.2 ml, 40 mmol). After the addition had been completed, the reaction mixture was stirred at room temperature for 16.5 hours. The reaction mixture was then treated with 1N sodium hydroxide solution (aq) (90 ml), stirred for 1 hour and finally extracted with chloroform. The chloroform extracts were dried (MgSO4) and concentrated under vacuum. The residue was dissolved in water, made acidic (pH=2) by the dropwise addition of 3N hydrochloric acid at 0 and was washed with ether to remove the diprotected diamine. The aqueous portion was made basic (pH 10) with 5% sodium carbonate solution and was extracted with ethyl acetate to give 1.6 g (20%) of mono-Boc-1,5-diaminopentane. |
1.6 g (20%) | With hydrogenchloride; sodium hydroxide; In water; tert-butyl alcohol; | EXAMPLE 9 Preparation of: STR13 1,5-Diaminopentane (14.0 ml, 120 mmol) was dissolved in tert.-butanol(70 ml) and was treated dropwise over a period of 10 min with di-tert-butyl dicarbonate (9.2 ml, 40 mmol). After the addition had been completed, the reaction mixture was stirred at room temperature for 16.5 hr. The reaction was then treated with lN sodium hydroxide solution (aq) (90 ml), stirred for 1 hr and finally extracted with chloroform. The chloroform extracts were dried (MgSo4) and concentrated under vacuum. The residue was dissolved in water, made acidic (pH=2) by the dropwise addition of 3N hydrochloric acid at 0 and was washed with ether to remove the diprotected diamine. The aqueous portion was made basic (pH 10) with 5% sodium carbonate solution and was extracted with ethyl acetate to give 1.6 g (20%) of mono-Boc 1,5-diaminopentane. The structure was confirmed by 'H NMR and CI-MS. To a solution of the heptapeptide prepared in Example 8 and mono-Boc-1,5-diaminopentane in dimethylformamide, dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate is added. |
With triethylamine; In dichloromethane; at 0℃; | General procedure: The diamine (0.2 mol) and TEA (0.5 equiv.) was added into a 250 mL flask. Then the solutionof (Boc)2O (0.3 equiv.) in dicholomethane was dropped into the mixture at ice bath. Uponcompletion, the reaction solution was filtrated to remove the generated white solid.Dicholomethane was evaporated under vacuum. The residue was dissolved in ethyl acetate andwashed with the distilled water (10 mL × 3). The organic solvent was dried with MgSO4, thenevaporated under vacuum to afford the crude product. The residue was purified using columnchromatography (ethyl acetate : petroleum ethyl V/V 2:1 ) to afford the Boc protected diamine i.Compound i (10 mmol) and 4-tert-butylphenyl isothiocyanate (1.0 equiv.) was added into a 50mL flask, TEA (10 mL) as the solvent. Then the solution was stirred at room temperature. Afterthe completion of the reaction monitored by TLC, the distilled water was added into to terminatethe reaction. The solution was extracted with ethyl acetate, then washed with the distilled water(10 mL × 3) to remove TEA. The organic solvent was dried with MgSO4, then evaporated undervacuum to afford the crude product ii (white solid).Compound ii (10 mmol) was added into the mixture of ethyl acetate and trifluoroacetic acid(V/V 2:1) in a 50 mL flask. The solution was stirred at room temperature under N2 atmosphere.After the completion of the reaction monitored by TLC, the reaction solution was neutralized withNa2CO3, then the dicholomethane was evaporated under vacuum. The residue was dissolved inethyl acetate and washed with the distilled water (10 mL × 3). The organic solvent was dried withMgSO4, and evaporated under vacuum. The crude product was purified using columnchromatography (ethyl acetate: methanol V/V 1:1) to afford the orange oil 6(a-e). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere; | To a solution of 21 (40 mg, 0.20 mmol) in anhydrous THF (5 mL),HBTU (81 mg, 0.20 mmol), DIPEA (50 mL, 0.20 mmol) and a solutionof D-()-biotin (50 mg, 0.20 mmol) in anhydrous THF (5 mL) wereadded. The mixturewas stirred at room temperature for 24 h underan atmosphere of argon, and then it was concentrated underreduced pressure. The residue was diluted with CH2Cl2 and washedwith 1M HCl (aq), saturated NaHCO3 (aq) and brine. The organicphase was dried over Na2SO4, filtered, and purified by silica gelchromatography (eluted with CH2Cl2/MeOH 30:1, v/v) to affordcompound 22 as yellow powder (50 mg, 65% yield). Mp:210.2e210.4 C. 1H NMR (400 MHz, DMSO-d6) delta 7.77 (s, 1H), 6.80 (s,1H), 6.47 (s, 1H), 6.40 (s, 1H), 4.32 (s, 1H), 4.15 (s, 1H), 3.11 (s, 1H),3.01 (s, 2H), 2.89e2.83 (m, 21H) [34]. ESI-MS (m/z): 429.3 (M H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | Example 29: synthesis of N-(5-amino-pentyl)-N-methyl-2-nitro-benzenesulfonamide (31)DIPEA, DCM 29-1 <n="112"/>To a solution of (5-amino-pentyl)-carbamic acid tert-butyl ester (Ig, 4.94 mmol) in DCM (10 rnL) were added 2-nitrobenzene sulfonyl chloride (1.15g, 1.05 eq) and DIPEA (0.958g, 1.5 eq) at room temperature. After Ih, the reaction mixture was diluted with water, washed with a solution of aqueous citric acid, dried over magnesium sulphate, filtered and concentrated to give 1.9 Ig (quantitative yield) of the target product 29-1, which was used without any further purification in the next step, m/z = 388 (M+H)+. |
85% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | 30a 30b 30cTo a solution of tert-butyl 5-aminopentylcarbamate 30a (20 g, 99 mmoles) and 2- nitrobenzene-1-sulfonyl chloride 30b (23 g, 1.05 eq) in DCM (200 mL) was added dropwise diisopropyl ethyl amine (19.2 g, 1.5 eq) at 0C. After stirring at RT overnight, the RM was successively washed with an aqueous solution of citric acid, then brine, dried over magnesium sulfate, filtered and concentrated. Trituration in diisopropyl ether afforded 32.61 g (85% yield) of tert-butyl 5-(2- nitrophenylsulfonamido)pentylcarbamate 30c as a white solid; m/z 388 [M+H]+. |
85% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Example 12: Synthesis of Lambda/-(5-aminopentyl)-Lambda/-methyl-2-nitrobenzenesulfonamide 16; Step 155To a cooled solution of tert-butyi (5-aminopentyl)carbamate (20 g, 99 mmol) in dichloromethane 250 mL 2-nitrobenzene-l-sulfonyl chloride (23 g, 104 mmol) was added. The resulting mixture was stirred at 00C then diisopropylethylamine (19.7 g, 144 mmol) was added drop wise. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured in water and citric acid the organic layer was separated and successively dried over MgSO4 filtered and concentrated to yield 32.6 g (85%) of tert-butyl (5-[(2-nitrophenyl)sulfonyl]amino}pentyl) carbamate 55 as white needles m/z 388 [M+H]+. |
With triethylamine; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere; | Ex. 6(F). HT01. A solution of N-Boc-cadaverine (0.50 g, 2.48 mmol) in THF (10 mL) was treated with o-nitrophenylsulfonyl chloride (0.55 g, 2.48 mmol) and Et3N (0.51 mL, 3.71 mmol), and the mixture was stirred for lh at room temperature. The mixture was poured into H20 and extracted with ethyl acetate. The organic layer was washed with H20 and brine, dried over Na2S04 and concentrated under reduced pressure. The residue was dissolved in CH3CN (20 ml), and Cs2C03 (2.40 g, 7.43 mmol) and phenethylbromide (0.69 g, 3.71 mmol) was added. The mixture was stirred for 2 h at 80 C. The mixture was poured into H20 and extracted with ethyl acetate. The organic layer was washed with H20 and brine, dried over Na2S04 and concentrated under reduced pressure. Chromatography (50 g; ethyl acetate :hexane=l :2) afforded sulfonamide (1.1 g, 91%). 1H NMR (CDC13, 300 MHz) delta = 7.96 (m, 1H), 7.30-7.15 (m, 5H), 4.50 (br, 1H), 3.50 (m, 2H), 3.33 (t, 2H, J = 7.5 Hz), 3.07 (q, 2H, J = 6.7 Hz), 2.84 (m, 2H), 1.65-1.38 (m, 4H), 1.44 (s, 9H), 1.34-1.20 (m, 2H). 13C NMR (CDC13, 100 MHz) delta = 156.33, 148.38, 138.39, 133.98, 133.74, 131.96, 131.03, 129.13, 128.97, 127.03, 124.53, 79.48, 49.15, 47.96, 40.63, 35.48, 29.98, 28.79, 28.10, 24.04. HRMS calculated for C24H34N306S [M+H]+492.2163, found 492.2169. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-chloro-1,3-dimethylimidazolinium chloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; | 1.1 To a 2-dram vial were added (5-amino-pentyl)-carbamic acid tert-butyl ester (0.04 g, 0.2 mmol) and l-(3-chloro-benzyl)-2-oxo-l,2-dihydro-pyridine-3-carboxylic acid (0.047 g, 0.2 mmol) in 2 ml of CH3CN. To this mixture were added 2-chloro-l,3-dimethylimidazolinium chloride (0.037 g, 0.22 mmol) and di-isopropyl-ethylamine (0.031 g, 0.24 mmol). The vial was capped and shaken at room temperature overnight. The solvent was removed using solvent evaporator GeneVac HT-12. To this vial were added 3 ml and 1.5 ml of water. The vial was shaken vigorously and the water was removed. The organic solvent was removed using the GeneVac HT-12 to give the oily liquid Compound 1.1. ES (+) MS m/e = 448 (M+l). | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 17h; | 2.1 l-(3-Chloro-benzyl)-2-oxo-l,2-dihydro-pyridine-3-carboxylic acid (2.59 grams, 9.82 mmol) was combined withN-(3-dimethylaminopropyl)-N'-ethylcarbodiimde hydrochloride (2.07 grams, 10.80 mmol) and 1-hydroxybenzotriazole monohydrate (1.65 grams, 10.80 mmol) in DMF (25 ml). (5-Amino-pentyl)-carbamic acid tert-butyl ester (1.99 grams, 9.82 mmol) dissolved in DMF (25 ml) was added followed by diisopropylethylamine (6.0 ml, 34.37 mmol). The reaction was stirred at ambient temperature for 17 hours, concentrated, and EtOAc was added. The reaction mixture was washed with IM sodium hydrogen sulfate monohydrate, saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated to give 3.76 grams of Boc protected intermediate which was used without further purification. This was dissolved in DCM (20 ml) and 4.0 M HCL p-dioxane (21 ml) was added. After stirring at ambient temperature for 1 hour, the solvents were removed to give Compound 2.1 (3.20 grams, 8.33 mmol, 85%). IH NMR (400 MHz, DMSO-d6) δ ppm 1.31 (m, 2 H) 1.52 (m, 4 H) 2.73 (m, 2 H) 3.26 (m, 2 H) 5.24 (m, 2 H) 6.57 (m, 1 H) 7.25 (m, 1 H) 7.37 (m, 3 H) 8.09 (br. s., 3 H) 8.27 (m, 1 H) 8.34 (m, 1 H) 9.63 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With N-ethyl-N,N-diisopropylamine; In iso-butanol; at 160℃; for 0.333333h;Microwave irradiation;Product distribution / selectivity; | 2-Chloro-4-methoxy-pyrimidine (1.09 grams, 7.51 mmol) and (5-amino-pentyl)- carbamic acid tert-butyl ester (1.52 grams, 7.51 mmol) and diisopropylethylamine (6.54 ml, 37.6 mmol) were combined in sec-butanol (10 ml) and heated to 160 0C by microwave irradiation for 20 minutes. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography on silica (5% MeOH/DCM) to yield Compound 6.1 (0.459 grams, 1.48 mmol, 20%). IH NMR (400 MHz, MeOH-d4) delta ppm 1.26 (m, 2 H) 1.31 (m, 9 H) 1.39 (m, 2 H) 1.50 (m, 2 H) 2.92 (m, 2 H) 3.22 (m, 2 H) 3.76 (m, 3 H) 5.87 (m, 1 H) 7.78 (m, 1 H). |
With potassium carbonate; N-ethyl-N,N-diisopropylamine; In iso-butanol; at 140℃; for 16h;Product distribution / selectivity; | To a 2-dram vial were added (5-amino-pentyl)-carbamic acid tert-butyl ester (0.04 g, 0.2 mmol) and <strong>[22536-63-6]2-chloro-4-methoxy-pyrimidine</strong> (0.029 g, 0.2 mmol) in 2 ml of S-BuOH and 0.2 ml of di-isopropylethylamine. The vial was capped and shaken at 1400C for 16 hours. The <n="51"/>solvent was filtered and removed using the GeneVac HT- 12 to give Compound 7.3. ES (+) MS m/e = lll (M+l). | |
With N-ethyl-N,N-diisopropylamine; In iso-butanol; at 135℃; for 16h;Product distribution / selectivity; | <strong>[22536-63-6]2-Chloro-4-methoxypyrimidine</strong> (Aldrich, 0.144 g, 1 mmol) and N-(5- aminoamyl)carbamicacid tert-butylester (TCI, 0.202 g, 1 mmol) were mixed in 2-butanol and N,N-diisopropylethylamine (0.7 ml, 4 mmol) were added. The reaction was heated at 135 0C for 16 hours and the solvent was removed in vacuo to yield clear gel. This gel was disso loved in 2 ml of dichloroethane and 1 ml methanol, to which was added 1 ml of 4.0 M HCl in para-dioxane. The reaction was stirred for 2 hours at room temperature and the solvent was evaporated to dryness. ES (+) MS m/e = 211 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium carbonate; In dichloromethane; at 20 - 40℃; for 12h; | [117] To a solution of t-butyl (5-aminopentyl) carbamate (16) (1.00 g, 4.94 mmol) in di- chloromethane (100 ml) was slowly dropped benzyl bromide (1.99 ml, 16.81 mmol) and sodium carbonate (2.24 g, 26.69 mmol) at room temperature. The resulting reaction mixture was stirred at 40 0C for 12 hours and extracted with dichloromethane three times. Then, the combined organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate :hexane: dichloromethane = 1:10:1) to give the target compound as a yellow liquid (0.92 g, 49 %).[118] 1H NMR (400 MHz, CDCl3) delta 7.40-7.23 (m, 1OH, aromatic), 3.57 (s, 4H, -(Bn)2), 3.09-3.07 (m, 2H, HN-CH2-), 2.44 (t, J = 7.05 Hz, 2H, -CH2-N-), 1.58-1.51 (m, 2H, HN-CH2-CH2-), 1.48 (s, 9H, (CHs )3C-O), 1.41-1.27 (m, 4H, HN-CH2-CH2-CH2-CH2 -CH2-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.02 g | Stage #1: 9-Ethyl-9H-carbazole-3-carboxylic acid; 5-tert-butoxycarbonylamino-1-aminopentane With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 6h; Stage #2: With hydrogenchloride In 1,4-dioxane at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
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93% | To a solution of 2 g (9.9 mmol) (5-Amino-pentyl)-carbamic acid tert-butyl ester in 40 ml THF at 0 C. was added 896 mul (14.83 mmol) CS2 and allowed to stir at room temperature for 14 h. 623 mg (14.83 mmol) cyanamide and 4 drops NEt3 was added and the mixture was heated to 4 C. for 3 h.The mixture was extracted with diethyl ether and the combined organic layers were dried with MgSO4.After filtration and removal of the volatiles the residue was purified by flash column chromatography on silica eluding with ethyl acetate/cyclohexane 1:1.The evaporation of the product fractions yielded 2.24 g (93%) of the title compound. 1-H-NMR (250 MHz, CDCl3) delta=4.58 (s, br, 1H, NH), 3.52 (t, J=6.5 Hz, 2H, NCH2), 3.13 (dd, J1=6.5 Hz, J2=4 Hz, 2H, NHC2), 1.74 (m, 2H, CH2), 1.50 (m, 4H, CH2), 1.44 (s, 9H, CH3). MS (m/e): 262.3 (M+NH4, 100%) |
Yield | Reaction Conditions | Operation in experiment |
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With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 1h; | 1 EXAMPLE 1; N-a-t-butyloxycarbonyl-d,l-tryptophan-[5-amino-(N-t-butyloxycarbonyl)-n-pentanyl]amide To a stirred solution of mono-N-Boc-1,5-pentanediamine (1.27 g, 6.3 mmol) and d,l-tryptophan (2.12 g, 7.0 mmol) in 30 mL THF is added dicyclohexylcarbodiimide (DCC) (1.54 g, 7.5 mmol) at room temperature. After one hour the mixture is filtered to remove the precipitated dicyclohexylurea and concentrated in vacuo. Ether is added, the mixture is filtered and then cooled, whereupon the product crystallizes out of solution. Filtration yields the product 1 as a light brown powder; mp. 97-98°. |
Yield | Reaction Conditions | Operation in experiment |
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100% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | Preparation 62 2-Chloroethanesulfonic Acid (5-tert-Butoxycarbonylaminopentyl)amide To a stirred solution of 5-(tert-butoxycarbonylamino)pentylamine (1.00 g, 4.94 mmol) and triethylamine (689 muL g, 4.94 mmol) in dichloromethane (22 ML) at 0 C. was added 2-chloro-1-ethanesulfonyl chloride (470 muL, 4.50 mmol).The reaction mixture was stirred for 2 h at room temperature and then washed with saturated aqueous sodium bicarbonate solution (15 ML).The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to give the title compound (100% yield), which was used in the next step without further purification. |
100% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | Preparation 24 2-Chloroethanesulfonic Acid (5-tert-Butoxycarbonylaminopentyl)amide To a stirred solution of 5-(tert-butoxycarbonylamino)pentylamine (1.00 g, 4.94 mmol) and triethylamine (689 muL g, 4.94 mmol) in dichloromethane (22 mL) at 0 C. was added 2-chloro-1-ethanesulfonyl chloride (470 muL, 4.50 mmol). The reaction mixture was stirred for 2 h at room temperature and then washed with saturated aqueous sodium bicarbonate solution (15 mL). The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to give the title compound (100% yield), which was used in the next step without further purification. |
100% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | To a stirred solution OF 5-(TERT-BUTOXYCARBONYLAMINO) pentylamine (1.00 g, 4.94 mmol) and triethylamine (689 UL g, 4. 94 mmol) in dichloromethane (22 mL) at 0 C was added 2-CHLORO-1-ETHANESULFONYL chloride (470 LL, 4.50 mmol). The reaction mixture was stirred for 2 h at room temperature and then washed with saturated aqueous sodium bicarbonate solution (15 mL). The organic layer was dried (NA2S04) and the solvent was removed under reduced pressure to give the title compound (100% yield), which was used in the next step without further purification. |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | To a stirred solution of 5-(tert-butoxycarbonylamino)pentylamine (1.00 g, 4.94 mmol) and triethylamine (689 muL g, 4.94 mmol) in dichloromethane (22 mL) at 0 C. was added 2-chloro-1-ethanesulfonyl chloride (470 muL, 4.50 mmol). The reaction mixture was stirred for 2 h at room temperature and then washed with saturated aqueous sodium bicarbonate solution (15 mL). The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to give the title compound (100% yield), which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In water; acetone; at 20℃; for 1h; | 1a Production of [5-(3-Nitro-benzenesulfonylamino)-pentyl]-carbamic acid-tert-butyl ester 4.2 ml (30.1 mmol) of triethylamine is added to a solution of 3.21 g (14.5 mmol) of 3-nitrobenzenesulfonyl chloride and 3.0 ml (14.4 mmol) of N-Boc-1,5-diaminopentane in 50 ml of acetone and 15 ml of water. The reaction mixture is stirred for one hour at room temperature. Then, the acetone is drawn off in a rotary evaporator. After water (20 ml) is added, it is extracted with ethyl acetate (2*). The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. 5.00 g (12.9 mmol, corresponding to 90% of theory) of the product is obtained as a light yellow oil. 1H-NMR (DMSO): 8.49 (m, 2H), 8.19 (dd, 1H), 7.88 (m, 2H), 6.72 (t, 1H), 2.82 (m, 4H), 1.32 (m, 15H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In dimethyl sulfoxide; at 105℃; for 6h; | Preparation 21 {5-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethyl-silanyloxy)ethylamino]pentyl}carbamic Acid tert-Butyl Ester The product of Preparation 13 (600 mg, 1.23 mmol) and <strong>[51644-96-3]N-tert-butoxycarbonyl-1,5-diaminopentane</strong> (622 mg, 3.07 mmol) were dissolved in dimethyl sulfoxide (1.23 ML) and heated to 105 C. for 6 h.The reaction mixture was then cooled and diluted with ethyl acetate (10 ML) and washed with saturated aqueous sodium bicarbonate solution (4 ML).The organic phase was dried (magnesium sulfate) and the solvent was removed under reduced pressure.The crude residue was purified by column chromatography (5-10% methanol/dichloromethane) to give the title compound (~100% yield). |
~ 100% | With dimethyl sulfoxide; at 105℃; for 6h; | The product of Preparation 11 (600 mg, 1.23 mmol) AND N-TERT-BUTOXYCARBONYL- 1, 5-DIAMINOPENTANE (622 mg, 3.07 mmol) were dissolved in dimethyl sulfoxide (1.23 mL) and heated to 105 C for 6 h. The reaction mixture was then cooled and diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium bicarbonate solution (4 mL). The organic phase was dried (magnesium sulfate) and the solvent was removed under --88-- reduced pressure. The crude residue was purified by column chromatography (5-10% methanol/dichloromethane) to give the title compound (-100% yield). |
96% | In dimethyl sulfoxide; at 105℃; for 6h; | Intermediate 51. tert-butyl {5-[((2R)-2-[8-(benzyloxy)-2-oxo-1 ,2-dihydroquinolin-5-yl]-2-[tert- butyl(dimethyl)silyl]oxy}ethyl)amino]pentyl}carbamate 8-(benzyloxy)-5-((1 R)-2-bromo-1 -[tert-butyl(dimethyl)silyl]oxy}ethyl)quinolin-2(1 H)-one (prepared according to US200400591 16, 482mg, 0.99mmol) and tert-butyl-5- aminopentylcarbamate (0.51 mL, 2.47mmol) were dissolved in DMSO (1 mL) and the mixture was heated to 105 C over a period of 6 hours. Then, ethyl acetate was added and the organic phase was washed with 4% aqueous sodium bicarbonate solution. The organic phase was dried, filtered and concentrated to dryness. The residue was purified by column chromatography over silica gel eluting with a gradient of dichloromethane and dichloromethane/methanol (95:5) to afford the title compound (581 mg, 96%) as a colorless oil. LRMS (m/z): 610 (M+1 )+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | To a solution of 1 ,1-dimethylethyl (5-aminopentyl)carbamate (0.204 mL, 1.01 mmol) in anhydrous 1 ,2-dichloroethane (2.5 mL) was added 6,7-dihydroquinolin-8(5/-/)-one (0.1 g, 0.679 mmol), and acetic acid (0.058 mL, 1.01 mmol) and stirred for 20 minutes. Sodium triacetoxyborohydride (0.216 g, 1.01 mmol) was added and mixture was stirred at room temperature overnight. 10% Aqueous sodium carbonate was added and the resulting mixture was stirred vigorously for 30 minutes. The organic layer was washed with saturated brine and then the combined aqueous layers were washed with dichloromethane. The combined organics were dried over magnesium sulfate and concentrated to a brown oil that was purified by silica gel chromatography (0-10% 2N methanolic ammonia in dichloromethane) to afford 0.2Og (89% yield) of 1 ,1-dimethylethyl [5-(5,6,7,8-tetrahydro-8-quinolinylamino)pentyl] carbamate as a yellow oil. 1H NMR (DMSO): delta 8.39 (d, 1 H), 7.52 (d, 1 H), 7.25 (m, 1 H), 6.80 (t, 1 H), 4.13 (d, 1 H), 3.68 (t, 1 H), 3.20 (d, 1 H), 2.92 (m, 2H), 2.76 (m, 2H), 2.66 (m, 2H), 2.04 (m, 1 H), 1.93 (m, 1 H), 1.67 (m, 2H), 1.24-1.53 (m, 13H). MS m/z 334 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 3h; | Dissolve 1.00 g (3.0 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 5 ml DMF and add 1.15 g (8.9 mmol) DIEA. Add 1.20 g (5.9 mmol) 5-[(tert.-butyloxycarbonyl)amino]-1-pentylamine [obtainable from 1,5-diaminopentane according to J. Med. Chem. 47 (20), 4933-4940 (2004)] and then heat the mixture to 80 C. for 3 h. After cooling, dilute the mixture with dichloromethane and wash successively with water and saturated sodium chloride solution. Dry the organic phase over magnesium sulphate and concentrate by evaporation. Purify the residue by RP-HPLC (column: Gromsil 250 mm*30 mm, 10 mum; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%?98% acetonitrile, 50-55 min 98% acetonitrile). A total of 1.07 g (67% of theor.) of tert.-butyl-(5-[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}pentyl)carbamate is obtained in two fractions, in the form of beige crystals. LC-MS (Method 2): Rt=2.85 min; m/z=503 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine; In acetonitrile; at 20℃; | a) l-phenoxybenzenesulfonamido-5-(Boc-amino)pentane; To a solution of 5-(Boc-amino)pentylamine (12.8 mmol) and Et3N (2 eq, 3.55 ml, 25.6 mmol) in 30 ml CH3CN was added dropwise 4-phenoxybenzenesulfonyl chloride solution (1.1 eq5 3.44 g, 14 mmol) in 20 ml CH3CN. The reaction was stirred overnight at room temperature. The precipitate was filtered and the solvent was evaporated. The product was purified by silica gel chromatography [eluent: CH2Cl2 / 1-2% MeOH] to yield 3.7 g (67%) pale yellow oil.NMR (CDCl3) 1H: 1.26-1.15 (m, 6H, 3 x CH2), 1.45 (s, 9H, Boc), 2.92 (t, J = 6.6 Hz3 2H, CH2), 3.05 (q, J = 6.6 Hz, 2H, CH2), 4.55 (s, 1H, NH), 4.81(t, 1H, NH)5 7.05 (dd, J= 8.7 Hz5 4H)5 7.2 (t, J= 7.5 Hz, 1H), 7.4 (t, J= 8.1 Hz5 2H)5 7.8 (d5 J = 9.0 Hz5 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference compound H: 1 ,1 -dimethylethyl [5-([(4S)-6-(4-chlorophenyl)-1 -methyl-8- (methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4- yl]acetyl}amino)pentyl]carbamate A mixture of [(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 .2,4]triazolo[4,3- a][1 ,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound G) (1 .0g, 2.5mmol), HATU (1 .9g, 5mmol) and DIPEA (0.88ml, 5mmol) was stirred for 80 minutes at room temperature, to this was added 1 ,1 -dimethylethyl (4- aminobutyl)carbamate (1 .05ml, 5.0mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2h before it was concentrated. The residue was taken up in dichloromethane and washed with 1 N HCI. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1 N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/ methanol 95/5 to give the title compound as a yellow solid (1 .2g). LC/MS (Method D): rt = 3.04 min. | ||
Reference compound I: 1 ,1 -dimethylethyl [5-([(4S)-6-(4-chlorophenyl)-1 -methyl-8- (methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4- yl]acetyl}amino)pentyl]carbamate A mixture of [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1 .2,4]triazolo[4,3- a][1 ,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound H) (1.0g, 2.5mmol), HATU (1.9g, 5mmol) and DIPEA (0.88ml, 5mmol) was stirred for 80 minutes at room temperature, to this was added 1 ,1-dimethylethyl (4- aminobutyl)carbamate (1 .05ml, 5.0mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2h before it was concentrated. The residue was taken up in dichloromethane and washed with 1 N HCI. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1 N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/ methanol 95/5 to give the title compound as a yellow solid (1.2g). LC/MS (Method A): rt = 3.04 min. | ||
Reference compound I: 1 ,1 -dimethylethyl [5-([(4S)-6-(4-chlorophenyl)-1 -methyl-8- (methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4- yl]acetyl}amino)pentylA mixture of [(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 .2,4]triazolo[4,3- a][1 ,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound H) (1 .0g, 2.5mmol), HATU (1 .9g, 5mmol) and DIPEA (0.88ml, 5mmol) was stirred for 80 minutes at room temperature, to this was added 1 ,1 -dimethylethyl (4- aminobutyl)carbamate (1 .05ml, 5.0mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2h before it was concentrated. The residue was taken up in dichloromethane and washed with 1 N HCI. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1 N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/ methanol 95/5 to give the title compound as a yellow solid (1 .2g). LC/MS (Method D): rt = 3.04 min. |
Reference compound H: 1 ,1 -dimethylethyl [5-([(4S)-6-(4-chlorophenyl)-1 -methyl-8- (methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4- yl]acetyl}amino)pentyl]carbamate; A mixture of [(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 .2,4]triazolo[4,3- a][1 ,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound G) (1 .0g, 2.5mmol), HATU (1 .9g, 5mmol) and DIPEA (0.88ml, 5mmol) was stirred for 80 minutes at room temperature, to this was added 1 ,1 -dimethylethyl (4- aminobutyl)carbamate (1 .05ml, 5.0mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2h before it was concentrated. The residue was taken up in dichloromethane and washed with 1 N HCI. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1 N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/ methanol 95/5 to give the title compound as a yellow solid (1 .2g). LC/MS (Method D): rt = 3.04 min. | ||
Reference compound I: 1 ,1 -dimethylethyl [5-([(4S)-6-(4-chlorophenyl)-1 -methyl-8- (methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4- yl]acetyl}amino)pentyl]carbamate A mixture of [(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 .2,4]triazolo[4,3- a][1 ,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound H) (1 .0g, 2.5mmol), HATU (1 .9g, 5mmol) and DIPEA (0.88ml, 5mmol) was stirred for 80 minutes at room temperature, to this was added 1 ,1 -dimethylethyl (4- aminobutyl)carbamate (1 .05ml, 5.0mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2h before it was concentrated. The residue was taken up in dichloromethane and washed with 1 N HCI. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1 N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/ methanol 95/5 to give the title compound as a yellow solid (1 .2g). LC/MS (Method D): rt = 3.04 min. | ||
Reference compound H: 1 ,1 -dimethylethyl [5-([(4S)-6-(4-chlorophenyl)-1 -methyl-8- (methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4- yl]acetyl}amino)pentylA mixture of [(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3- a][1 ,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound G) (1 .0g, 2.5mmol), HATU (1 .9g, 5mmol) and DIPEA (0.88ml, 5mmol) was stirred for 80 minutes at room temperature, to this was added 1 ,1 -dimethylethyl (4- aminobutyl)carbamate (1 .05ml, 5.0mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2h before it was concentrated. The residue was taken up in dichloromethane and washed with 1 N HCI. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1 N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/ methanol 95/5 to give the title compound as a yellow solid (1 .2g). LC/MS (Method D): rt = 3.04 min. | ||
A mixture of [(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3- a][1 ,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound H) (1.0g, 2.5mmol), HATU (1.9g, 5mmol) and DIPEA (0.88ml, 5mmol) was stirred for 80 minutes at room temperature, to this was added 1 ,1-dimethylethyl (4-aminobutyl)carbamate (1.05ml, 5.0mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2h before it was concentrated. The residue was taken up in dichloromethane and washed with 1 N HCI. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1 N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash- chromatography on silica using dichloromethane/ methanol 95/5 to give the title compound as a yellow solid (1 .2g). LC/MS (Method A): rt = 3.04 min. | ||
REFERENCE COMPOUND I 1,1-dimethylethyl [5-([(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetyl}amino)pentyl]carbamate A mixture of [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound H) (1.0 g, 2.5 mmol), HATU (1.9 g, 5 mmol) and DIPEA (0.88 ml, 5 mmol) was stirred for 80 minutes at room temperature, to this was added 1,1-dimethylethyl (4-aminobutyl)carbamate (1.05 ml, 5.0 mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2 h before it was concentrated. The residue was taken up in dichloromethane and washed with 1N HCl. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/methanol 95/5 to give the title compound as a yellow solid (1.2 g). LC/MS (Method A): rt=3.04 min. | ||
Reference Compound H: 1,1-dimethylethyl [5-([(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetyl}amino)pentyl]carbamate A mixture of [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound G) (1.0 g, 2.5 mmol), HATU (1.9 g, 5 mmol) and DIPEA (0.88 ml, 5 mmol) was stirred for 80 minutes at room temperature, to this was added 1,1-dimethylethyl (4-aminobutyl)carbamate (1.05 ml, 5.0 mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2 h before it was concentrated. The residue was taken up in dichloromethane and washed with 1N HCl. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/methanol 95/5 to give the title compound as a yellow solid (1.2 g). LC/MS (Method D): rt=3.04 min. | ||
A mixture of [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1 .2,4]triazolo[4,3- a][1 ,4]benzodiazepin-4-yl]acetic acid (for a preparation see Reference compound H) (1.0g, 2.5mmol), HATU (1.9g, 5mmol) and DIPEA (0.88ml, 5mmol) was stirred for 80 minutes at room temperature, to this was added 1 ,1-dimethylethyl (4- aminobutyl)carbamate (1 .05ml, 5.0mmol, available from Aldrich). The reaction mixture was stirred at room temperature for 2h before it was concentrated. The residue was taken up in dichloromethane and washed with 1 N HCI. The aqueous layer was extracted with dichloromethane twice. Organic layer was washed with 1 N sodium hydroxide, followed by a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The residue was purified by flash-chromatography on silica using dichloromethane/ methanol 95/5 to give the title compound as a yellow solid (1 .2g). LC/MS (Method D): rt = 3.04 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere; | To a 50-mL two-neck eggplant-shaped flask, (3- chlorosulfonyl) -benzoyl chloride (590 muL, 3.7 mmol, 2.5 eq) and 5 mL of dry methylene chloride were added. Tert-butoxycarbonyl (Boc) -1, 5-diaminopentane (300 mg, 1.5 mmol, 1 eq) and 5 mL of a dry methylene chloride solution of diisopropylethylamine (390 muL, 2.3 mmol,1.5 eq) were gradually added thereto in a water bath in an argon atmosphere. The mixture was further stirred at room temperature for 2 hours . The reaction was followed by TLC (SiO2/EtOAc : Hexane = 2 : 1) and completed when the production of the compound of interest was confirmed. The solvents were distilled off under reduced pressure using a vacuum pump. The residue was purified by column chromatography (SiO2/EtOAc : Hexane = 1 : 1). The solvents were distilled off under reduced pressure. The residue was vacuum-dried to obtain a clear oil. Identification was conducted by 1H-NMR. Experimental Results> Clear OilYield : 563 mg ( 90% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 12 h / 20 °C 2: dichloromethane / 2 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; | di-tert-butyl(((6,6'-disulfanediylbis(hexanoyl))bis(azanediyl))bis(pentane-5,l-diyl))dicarbamate (lb). In a solution of 6,6'-disulfanediyldihexanoic acid (250 mg, 0.849 mmol), tert-butyl (5-amino- pentyl)carbamate (412 mg, 2.038 mmol) and DIPEA (0.890 ml, 5.09 mmol) in DMF (4.7 ml), HBTU (1.29 g, 3.40 mmol) was added portionwise at room temperature. After stirring for 20 hours, the yellowish reaction mixture was diluted with ethyl acetate (70 ml) and washed with cold HC1 0. IN (3 x 50 ml), NaHC03 (sat) (1 x 50 ml) water (1 x 50 ml) and brine (lx 50 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using CHCl3/EtOH 95:5 to yield 525 mg (93%) of compound as a yellow sticky solid. lH NMR (400 MHz, CDC13): delta 5.87 (br, 2 H), 4.64 (br, 2 H), 3.22 (dt, J = 7.3 Hz, J2 = 6.8 Hz, 4H), 3.09 (dt, J = 8.1 Hz, J2 = 6.7 Hz, 4H), 2.65 (t, J = 7.2 Hz, 4H), 2.16 (t, J = 7.2 Hz, 4H), 1.73 - 1.59 (m, 8H), 1.55 - 1.45 (m, 8H), 1.42 (s, 18H), 1.37 - 1.28 (m, 4H). 13C NMR (100 MHz, CDC13): delta 172.9, 156.1, 79.0, 40.2, 39.2, 38.8, 36.5, 29.7, 29.1, 28.8, 28.4, 28.0, 25.3, 23.9. ESI- QTOF MS m/z calculated for C32H62N406S2 [M+H]+ 663.4184, measured 663.4185. |
93% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; | di-tert-butyl(((6,6?-disulfanediylbis(hexanoyl))bis(azanediyl))bis(pentane-5,1-diyl))dicarbamate(ib).In a solution of 6,6?-disulfanediyldihexanoic acid (250 mg, 0.849 mmol), tert-butyl (5-amino- pentyl)carbamate (412 mg, 2.038 mmol) and DIPEA (0.890 ml, 5.09 mmol) in DMF (4.7 ml), HBTU (1.29 g, 3.40 mmol) was added portionwise at room temperature. After stirring for 20 hours, the yellowish reaction mixture was diluted with ethyl acetate (70 ml) and washed with cold HC1 0.1N (3 x50 ml), NaHCO3 (sat) (1 x 50 ml) water (1 x 50 ml) and brine (lx 50 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using CHC13/EtOH 95:5 to yield 525 mg (93%) of compound as a yellow sticky solid. ?H NMR (400 MHz, CDC13): 5.87 (br, 2 H), 4.64 (br, 2 H), 3.22 (dt, J, = 7.3 Hz, J2 = 6.8 Hz, 4H), 3.09 (dt, J, = 8.1 Hz, J2 = 6.7 Hz, 4H), 2.65 (t, J= 7.2 Hz, 4H), 2.16 (t, J= 7.2 Hz, 4H),1.73 - 1.59 (m, 8H), 1.55 - 1.45 (m, 8H), 1.42 (s, 18H), 1.37 - 1.28 (m, 4H). ?3C NMR (100 MHz,CDC13): 172.9, 156.1, 79.0, 40.2, 39.2, 38.8, 36.5, 29.7, 29.1, 28.8, 28.4, 28.0, 25.3, 23.9. ESIQTOF MS m/z calculated for C32H62N40652 [M+H] 663.4184, measured 663.4185. |
93% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere; | In a solution of 6,6?-disulfanediyldihexanoic acid (250 mg, 0.849 mmol), tert-butyl (5-amino- pentyl)carbamate (412 mg, 2.038 mmol) and DIPEA (0.890 ml, 5.09 mmol) in DMF (4.7 ml), HBTU (1.29 g, 3.40 mmol) was added portionwise at room temperature. After stirring for 20 hours, the yellowish reaction mixture was diluted with ethyl acetate (70 ml) and washed with cold HC1 0. iN (3 x50 ml), NaHCO3 (sat) (1 x 50 ml) water (1 x 50 ml) and brine (lx 50 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using CHC13/EtOH 95:5 to yield 525 mg (93%) of compound as a yellow sticky solid. ?H NMR (400 MHz, CDC13): 5.87 (br, 2 H), 4.64 (br, 2 H), 3.22 (dt, J, = 7.3 Hz, J2 = 6.8 Hz, 4H), 3.09 (dt, J, = 8.1 Hz, J2 = 6.7 Hz, 4H), 2.65 (t, J= 7.2 Hz, 4H), 2.16 (t, J= 7.2 Hz, 4H),1.73 - 1.59 (m, 8H), 1.55 - 1.45 (m, 8H), 1.42 (s, 18H), 1.37 - 1.28 (m, 4H). ?3C NMR (100 MHz, CDC13): 172.9, 156.1, 79.0, 40.2, 39.2, 38.8, 36.5, 29.7, 29.1, 28.8, 28.4, 28.0, 25.3, 23.9. ESIQTOF MS m/z calculated for C32H62N40652 [M+H] 663.4184, measured 663.4185. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | tert-butyl (5-(2-azidoacetamido)pentyl)carbamate (12a): In a solution of 2-azidoacetic acid (50 mg, 0.495 mmol), tert-butyl (5-amino-pentyl)carbamate (120 mg, 0.594 mmol) and DIPEA (128 mg, 0.989 mmol) in DMF (2.7 ml), HBTU (225 mg, 0.594 mmol) was added slowly at room temperature. After stirring for 3 hours, the slight yellow solution was diluted with ethyl acetate (30 ml) and was washed with HC1 0.5 M (3 x 15 ml) and sat. NaHC03 (1 x 15 ml) solutions, water (1 x 15 ml) and brine (lx 15 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using chloroform/EtOH 95:5 to yield a clear colorless oil (128 mg, 91%). lH NMR (400 MHz, CDC13): delta 6.35 (br, 1 H), 4.55 (br, 1 H), 3.97 (s, 2 H), 3.28 (dt, J = 7.2 Hz, J2 = 6.9 Hz, 2H), 3.11 (dt, J = 7.8 Hz, J2 = 6.5 Hz, 2H), 1.61 - 1.47 (m, 4 H), 1.43 (s, 9H), 1.40 - 1.31 (m, 2H). 13C NMR (100 MHz, CDC13): delta 166.5, 156.0, 79.1, 52.7, 40.2, 39.2, 29.7, 29.0, 28.4, 23.9. |
91% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | tertbutvI (5(2azk1oacetamido)penty1)carbamate (12a):In a solution of 2-azidoacetic acid (50 mg, 0.495 mmol), tert-butyl (5-amino-pentyl)carbamate(120 mg, 0.594 mmol) and DIPEA (128 mg, 0.989 mmol) in DMF (2.7 ml), HBTU (225 mg, 0.594mmol) was added slowly at room temperature. After stirring for 3 hours, the slight yellow solutionwas diluted with ethyl acetate (30 ml) and was washed with HC1 0.5 M (3 x 15 ml) and sat. NaHCO3(1 x 15 ml) solutions, water (1 x 15 ml) and brine (lx 15 ml). The organic layer was dried undersodium sulfate, filtered and evaporated to dryness. The crude was purified by flash columnchromatography on silica using chlorofonn/EtOH 95:5 to yield a clear colorless oil (128 mg, 91%). ?H NMR (400 MHz, CDC13): 6.35 (br, 1 H), 4.55 (br, 1 H), 3.97 (s, 2 H), 3.28 (dt, J, = 7.2 Hz, J2 = 6.9 Hz, 2H), 3.11 (dt,J, = 7.8 Hz,J2 = 6.5 Hz, 2H), 1.61-1.47 (m, 4 H), 1.43 (s, 9H), 1.40-1.31 (m, 2H). ?3C NMR (100 MHz, CDC13): 166.5, 156.0, 79.1, 52.7, 40.2, 39.2, 29.7, 29.0, 28.4, 23.9. |
91% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere; | In a solution of 2-azidoacetic acid (50 mg, 0.495 mmol), tert-butyl (5-amino-pentyl)carbamate(120 mg, 0.594 mmol) and DIPEA (128 mg, 0.989 mmol) in DMF (2.7 ml), HBTU (225 mg, 0.594mmol) was added slowly at room temperature. After stirring for 3 hours, the slight yellow solutionwas diluted with ethyl acetate (30 ml) and was washed with HC1 0.5 M (3 x 15 ml) and sat. NaHCO3(1 x 15 ml) solutions, water (1 x 15 ml) and brine (lx 15 ml). The organic layer was dried undersodium sulfate, filtered and evaporated to dryness. The crude was purified by flash columnchromatography on silica using chlorofonn/EtOH 95:5 to yield a clear colorless oil (128 mg, 91%). ?H NMR (400 MHz, CDC13): 6.35 (br, 1 H), 4.55 (br, 1 H), 3.97 (s, 2 H), 3.28 (dt, J, = 7.2 Hz, J2 = 6.9 Hz, 2H), 3.11 (dt,J, = 7.8 Hz,J2 = 6.5 Hz, 2H), 1.61-1.47 (m, 4 H), 1.43 (s, 9H), 1.40-1.31 (m, 2H). ?3C NMR (100 MHz, CDC13): 166.5, 156.0, 79.1, 52.7, 40.2, 39.2, 29.7, 29.0, 28.4, 23.9. |
With sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; | tert-butyl (5-(2-azidoacetamido)pentyl)carbamate (12a) In a solution of 2-azidoacetic acid (50 mg, 0.495 mmol), tert-butyl (5-amino-pentyl)carbamate (120 mg, 0.594 mmol) and DIPEA (128 mg, 0.989 mmol) in DMF (2.7 ml), HBTU (225 mg, 0.594 mmol) was added slowly at room temperature. After stirring for 3 hours, the slight yellow solution was diluted with ethyl acetate (30 ml) and was washed with HCl 0.5 M (3*15 ml) and sat. NaHCO3 (1*15 ml) solutions, water (1*15 ml) and brine (1*15 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using chloroform/EtOH 95:5 to yield a clear colorless oil (128 mg, 91%). 1H NMR (400 MHz, CDCl3): delta 6.35 (br, 1H), 4.55 (br, 1H), 3.97 (s, 2H), 3.28 (dt, J1=7.2 Hz, J2=6.9 Hz, 2H), 3.11 (dt, J1=7.8 Hz, J2=6.5 Hz, 2H), 1.61-1.47 (m, 4H), 1.43 (s, 9H), 1.40-1.31 (m, 2H). 13C NMR (100 MHz, CDCl3): delta 166.5, 156.0, 79.1, 52.7, 40.2, 39.2, 29.7, 29.0, 28.4, 23.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Tert-butyl (5-(6-azidohexanamido)pentyl)carbamate (12b): HBTU (290 mg, 0.764 mmol) was slowly added to a solution of 6-azidohexanoic acid (100 mg, 0.636 mmol) and DIPEA (164 mg, 1.273 mmol) in DMF (3 ml) and the resulting solution was stirred for 15 min. A solution of tert-butyl (5-aminopentyl)carbamate (154 mg, 0.764 mmol) in DMF (0.5 ml) was then added dropwise and the reaction was stirred for 3 h. After this time, the reaction mixture was diluted with ethyl acetate (40 ml) and washed with HC1 0.5 M (3 x 20 ml) and sat. NaHCC>3 (1 x 20 ml) solutions, water (1 x 20 ml) and brine (lx 20 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using chloroform/EtOH 95:5 to yield a clear colorless oil (189 mg, 87%). iota¥ NMR (400 MHz, CDC13): delta 5.61 (br, 1 H), 4.58 (br, 1 H), 3.30 - 3.20 (m, 4 H), 3.10 (dt, J = 8.0 Hz, J, = 6.8 Hz, 2H), 2.16 (t, J= 7.4 Hz, 2H), 1.56 - 1.45 (m, 4 H), 1.56 - 1.45 (m, 4H), 1.43 (s, 9H), 1.41 - 1.29 (m, 4H). 13C NMR (100 MHz, CDC13): delta 172.7, 156.1, 79.1, 51.3, 40.2, 39.3, 36.5, 29.8, 29.2, 28.6, 28.4, 26.4, 25.2, 23.9. | |
87% | Tert-butyl (5-(6-azidohexanamido)pentyl)carbamate (12b): HBTU (290 mg, 0.764 mmol) was slowly added to a solution of 6-azidohexanoic acid (100 mg, 0.636 mmol) and DIPEA (164 mg, 1.273 mmol) in DMF (3 ml) and the resulting solution was stirred for 15 mm. A solution of tert-butyl (5-aminopentyl)carbamate (154 mg, 0.764 mmol) in DMF (0.5 ml) was then added dropwise and the reaction was stirred for 3 h. After this time, the reactionmixture was diluted with ethyl acetate (40 ml) and washed with HC1 0.5 M (3 x 20 ml) and sat. NaHCO3 (1 x 20 ml) solutions, water (1 x 20 ml) and brine (lx 20 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using chloroform/EtOH 95:5 to yield a clear colorless oil (189 mg, 87%). ?H NMR (400 MHz, CDC13): 5.61 (br, 1 H), 4.58 (br, 1 H), 3.30 - 3.20 (m, 4 H), 3.10 (dt, J, = 8.0Hz, J2 = 6.8 Hz, 2H), 2.16 (t, J= 7.4 Hz, 2H), 1.56 - 1.45 (m, 4 H), 1.56 - 1.45 (m, 4H), 1.43 (s, 9H),1.41 - 1.29 (m, 4H). ?3C NMR (100 MHz, CDC13): 172.7, 156.1, 79.1, 51.3, 40.2, 39.3, 36.5, 29.8,29.2, 28.6, 28.4, 26.4, 25.2, 23.9. | |
87% | HBTU (290 mg, 0.764 mmol) was slowly added to a solution of 6-azidohexanoic acid (100 mg, 0.636 mmol) and DIPEA (164 mg, 1.273 mmol) in DMF (3 ml) and the resulting solution was stirred for 15 mm. A solution of tert-butyl (5-aminopentyl)carbamate (154 mg, 0.764 mmol) in DMF (0.5 ml) was then added dropwise and the reaction was stirred for 3 h. After this time, the reactionmixture was diluted with ethyl acetate (40 ml) and washed with HC1 0.5 M (3 x 20 ml) and sat. NaHCO3 (1 x 20 ml) solutions, water (1 x 20 ml) and brine (lx 20 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using chloroform/EtOH 95:5 to yield a clear colorless oil (189 mg, 87%). ?H NMR (400 MHz, CDC13): 5.61 (br, 1 H), 4.58 (br, 1 H), 3.30 - 3.20 (m, 4 H), 3.10 (dt, J, = 8.0Hz, J2 = 6.8 Hz, 2H), 2.16 (t, J= 7.4 Hz, 2H), 1.56 - 1.45 (m, 4 H), 1.56 - 1.45 (m, 4H), 1.43 (s, 9H),1.41 - 1.29 (m, 4H). ?3C NMR (100 MHz, CDC13): 172.7, 156.1, 79.1, 51.3, 40.2, 39.3, 36.5, 29.8,29.2, 28.6, 28.4, 26.4, 25.2, 23.9. |
87% | With sodium hydrogencarbonate; In ethanol; water; N,N-dimethyl-formamide; | Tert-butyl (5-(6-azidohexanamido)pentyl)carbamate (12b) HBTU (290 mg, 0.764 mmol) was slowly added to a solution of 6-azidohexanoic acid (100 mg, 0.636 mmol) and DIPEA (164 mg, 1 273 mmol) in DMF (3 ml) and the resulting solution was stirred for 15 min. A solution of tert-butyl (5-aminopentyl)carbamate (154 mg, 0.764 mmol) in DMF (0.5 ml) was then added dropwise and the reaction was stirred for 3 h. After this time, the reaction mixture was diluted with ethyl acetate (40 ml) and washed with HC1 0.5 M (3*20 ml) and sat. NaHCO3 (1*20 ml) solutions, water (1*20 ml) and brine (1*20 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using chlorofomil EtOH 95:5 to yield a clear colorless oil (189 mg, 87%). 1H NMR (400 MHz, CDCl3): delta 5.61 (br, 1H), 4.58 (br, 1H), 3.30-3.20 (m, 4H), 3.10 (dt, J1=8.0 Hz, J2=6.8 Hz, 2H), 2.16 (t, J=7.4 Hz, 2H), 1.56-1.45 (m, 4H), 1.56-1.45 (m, 4H), 1.43 (s, 9H), 1.41-1.29 (m, 4H). 13C NMR (100 MHz, CDCl3): delta 172.7, 156.1, 79.1, 51.3, 40.2, 39.3, 36.5, 29.8, 29.2, 28.6, 28.4, 26.4, 25.2, 23.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 5h; | di-tert-butyl (((2,2?-disulfanediylbis(acetyl))bis(azanediyl))bis(pentane-5,1-diyl))dicarbamate(la).In a solution of 2,2?-disulfanediyldiacetic acid (160 mg, 0.878 mmol), tert-butyl (5-amino- pentyl)carbamate (391 mg, 1.932 mmol) and DIPEA (920 jil, 5.27 mmol) in DMF (4.9 ml), HBTU (1.33 g, 3.51 mmol) was added portionwise at room temperature. After stirring for 5 hours, the brownish solution was diluted with ethyl acetate (80 ml) and washed with water (3 x 30 ml) and brine(lx 30 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using CHC13/EtOH 95:5 to yield 420 mg (87%) of a yellow oil which solidified upon standing at room temperature. ?H NMR (400 MHz, CDC13): 6.91 (br, 2 H), 4.68 (br, 2 H), 3.44 (s, 4 H), 3.29 (dt, J, = 7.2 Hz, J2 = 6.8 Hz, 4H), 3.10 (dt, J, = 7.7 Hz, J2 = 6.3 Hz, 4H), 1.64 - 1.31 (m, 30 H). ?3C NMR (100 MHz, CDC13): 168.5, 156.1,79.1, 42.6, 40.2, 39.8, 29.7, 28.8, 28.4, 23.9. ESI-QTOF MS m/z calculated for C24H46N40652 [M+H]55 1.2932, measured 551.2921 |
87% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 5h; | di-tert-butyl (((2,2?-disulfanediylbis(acetyl))bis(azanediyl))bis(pentane-5,1-diyl))dicarbamate (la).In a solution of 2,2?-disulfanediyldiacetic acid (160 mg, 0.878 mmol), tert-butyl (5-amino- pentyl)carbamate (391 mg, 1.932 mmol) and DIPEA (920 jil, 5.27 mmol) in DMF (4.9 ml), HBTU(1.33 g, 3.51 mmol) was added portionwise at room temperature. After stirring for 5 hours, the brownish solution was diluted with ethyl acetate (80 ml) and washed with water (3 x 30 ml) and brine (lx 30 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using CHC13/EtOH 95:5 to yield 420 mg (87%) of a yellow oil which solidified upon standing at room temperature. ?H NMR (400 MHz,CDC13): 6.91 (br, 2 H), 4.68 (br, 2 H), 3.44 (s, 4 H), 3.29 (dt, J, = 7.2 Hz, J2 = 6.8 Hz, 4H), 3.10 (dt, J, = 7.7 Hz, J2 = 6.3 Hz, 4H), 1.64 - 1.31 (m, 30 H). ?3C NMR (100 MHz, CDC13): 168.5, 156.1, 79.1, 42.6, 40.2, 39.8, 29.7, 28.8, 28.4, 23.9. ESI-QTOF MS m/z calculated for C24H46N406S2 [M+H]55 1.2932, measured 551.2921 |
87% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 5h;Inert atmosphere; | In a solution of 2,2?-disulfanediyldiacetic acid (160 mg, 0.878 mmol), tert-butyl (5-amino- pentyl)carbamate (391 mg, 1.932 mmol) and DIPEA (920 jil, 5.27 mmol) in DMF (4.9 ml), HBTU(1.33 g, 3.51 mmol) was added portionwise at room temperature. After stirring for 5 hours, the brownish solution was diluted with ethyl acetate (80 ml) and washed with water (3 x 30 ml) and brine (lx 30 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using CHC13/EtOH 95:5 to yield 420 mg (87%) of a yellow oil which solidified upon standing at room temperature. ?H NMR (400 MHz,CDC13): 6.91 (br, 2 H), 4.68 (br, 2 H), 3.44 (s, 4 H), 3.29 (dt, J, = 7.2 Hz, J2 = 6.8 Hz, 4H), 3.10 (dt, J, = 7.7 Hz, J2 = 6.3 Hz, 4H), 1.64 - 1.31 (m, 30 H). ?3C NMR (100 MHz, CDC13): 168.5, 156.1, 79.1, 42.6, 40.2, 39.8, 29.7, 28.8, 28.4, 23.9. ESI-QTOF MS m/z calculated for C24H46N40652 [M+H]55 1.2932, measured 551.2921 |
87% | In N,N-dimethyl-formamide; | di-tert-butyl (((2,2'-disulfanediylbis(acetyl))bis(azanediyl))bis(pentane-5,1-diyl))dicarbamate (1a) In a solution of 2,2'-disulfanediyldiacetic acid (160 mg, 0.878 mmol), tert-butyl (5-amino-pentyl)carbamate (391 mg, 1.932 mmol) and DIPEA (920 mul, 5.27 mmol) in DMF (4.9 ml), HBTU (1.33 g, 3.51 mmol) was added portionwise at room temperature. After stirring for 5 hours, the brownish solution was diluted with ethyl acetate (80 ml) and washed with water (3*30 ml) and brine (1*30 ml). The organic layer was dried under sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography on silica using CHCl3/EtOH 95:5 to yield 420 mg (87%) of a yellow oil which solidified upon standing at room temperature. 1H NMR (400 MHz, CDCl3): delta 6.91 (br, 2H), 4.68 (br, 2H), 3.44 (s, 4H), 3.29 (dt, J1=7.2 Hz, J2=6.8 Hz, 4H), 3.10 (dt, J1=7.7 Hz, J2=6.3 Hz, 4H), 1.64-1.31 (m, 30H). 13C NMR (100 MHz, CDCl3): delta 168.5, 156.1, 79.1, 42.6, 40.2, 39.8, 29.7, 28.8, 28.4, 23.9. ESI-QTOF MS m/z calculated for C24H46N4O6S2 [M+H]+551.2932, measured 551.2921 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 1.5h; | To a mixture of methotrexate hydrate (50 mg, 110 umol), ED AC (63 mg, 330 umol) and triethylamine (77 uL, 550 umol) in 2 mL of DMF, N-Boc cadaverine (22 mg, 110 umol) was added. The reaction was stirred for 90 min then quenched with 2 mL of 1 N HCl diluted with water and subjected to preparative HPLC (20->50% MeCN in 0.1% aqueous formic acid). The appropriate fractions were concentrated and lyophilized to yield the desired product. Calculated for M+H: 639.3; found 639.5. <strong>[59-05-2]Methotrexate</strong> N-Boc-cadaverine adduct (24 mg, 38 umol) was treated with 4 M HCl in dioxane (0.5 mL) at RT. Upon completion of the reaction, the solvents were removed under reduced pressure, and the resulting residue was stirred with diethyl ether to form a yellow precipitate which was isolated by centrifugation. The hydrochloride salt was used without further characterization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran at -50 - 20℃; for 21h; | 2,2-dimethyl-4,12-dioxo-3,14-dioxa-5,ll-diazahexadecan-16-oic acid (12c): To a colorless/ transparent solution of glycolic anhydride (0.3 g, 3.26 mmol, 1.0 eq) in THF (6 mL) at -50°C, tert-butyl (5-aminopentyl)carbamate (0.7 ml, 0.66 g, 3.26 mmol, 1.0 eq) was added dropwise. The cold bath was removed and the reaction was allowed to stir at rt for 21 h. The solvent was removed in vacuum to provide 12c as light yellow oil (1.038 g, quant, yield). 1H NMR (400 MHz, DMSO-6) δ 7.80 (t, 5.6Hz, IH), 6.73 (t, 5.6Hz, IH), 4.07 (s, 2H), 3.93 (s, 2H), 3.06 (dd, 13.2Hz, 6.8Hz, 2H), 2.87 (dd,13.0Hz, 6.8Hz, 2H), 1.35 (s, 9H), 1,14-1.23 (m, 2H). 13C NMR (100 MHz) δ 171.49, 168.58, 155.59, 77.32, 70.19, 67.90, 38.10, 29.16, 28.82, 28.28, 23.67. MS(ESI)-TOF (negative) observed 317.2211 (M-l), required for C10H22N2O2 318.1791. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; In 1,4-dioxane; water; at 20℃; for 12h;Inert atmosphere; | A solution of 2-(Boc-oxyimino)-2-phenylacetonitrile (226 mg, 0.92 mmol) in 1,4-dioxane (30 mL) was added via syringe pump (rate=8 mL/hr) to a stirred solution of 1,5 diaminopentane dihydrochloride (1 g, 5.52 mmol) and TEA (1 ml, 7.12 mmol) in 1:1 1,4-dioxane:water (40 mL) under inert atmosphere at room temperature. The reaction was stirred for 12 h and DCM (20 mL) was added to the reaction mixture. The organic phase was extracted and concentrated in vacuo. The yellow residue was dissolved in diethyl ether (15 mL) and 5% HCl solution added. The acidic solution was washed with diethyl ether and then the pH of the aqueous layer adjusted to pH 14 with 2.5M NaOH solution. Ethyl acetate (20 mL) was added and the organic layer was washed with brine (2×50 mL), and dried (MgSO4). The solvents were evaporated in vacua to yield N-Boc-cadaverine as a yellow oil (100 mg, 55%). HPLC/MS (Hydrophilic/TFA) Rt=6.17 min; ESI MS (+ve) m/z=203 [M+1H); calc. m/z for C10H22N2O2: 202.3 g/mol, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | To a 100-mL two-neck eggplant-shaped flask, 3 , 5- bis (trifluoromethyl) -benzoic acid (500 mg, 1.94 mmol, 1 eq) , water-soluble carbodiimide (WSOHCl) (589 mg, 2.9 mmol, 1.5 eq) , and 5 mL of dry dimethylformamide were added. Then, the mixture was stirred at room temperature for 5 minutes in an argon atmosphere. Then, Boc-1, 5-diaminopentane (510 mg, 2.52 mmol, 1.3 eq) was added thereto. The mixture was stirred at room temperature for 8 hours in an argon atmosphere. The reaction was followed by TLC (SiO2/CHCl3 : MeOH = 10 : 1) and completed when the production of the compound of interest was confirmed. The solvents were distilled off under reduced pressure using a vacuum pump. After the addition of ethyl acetate (300 mL) , the organic phase was washed with an aqueous saturated sodium bicarbonate solution (100 mL, twice) and with a saturated saline (100 mL, twice) . The organic phase was dried over anhydrous magnesium sulfate. Insoluble matter was filtered off. Then, the solvents were distilled off under reduced pressure to obtain a white solid. Identification was conducted by 1H-NMR. Experimental Results> White Solid Yield: 628 mg (79%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | To a solution of 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetic acid (150 mg) in dichloromethane (15 ml) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide189 (108 mg) and DMAP (54.9 mg). After stirring at room temperature for 10 minutes, tert-butyl (5-aminopentyl)carbamate190 (75.7 mg) was added and the resulting solution was stirred at room temperature for 48 h. The reaction mixture was partioned between water and dichloromethane, 1 M aq. HCl was added and the mixture was separated. The organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0 to 5% of methanol in dichloromethane) to afford tert-butyl (5-(2-((6S)-4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamido)pentyl)carbamate (124mg, 57%) as a light brown oil. MS (ISP): 585.2 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
255 mg | 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 at 20℃; for 4h; | 356 mg (1.757 mmol) tert-butyl (5-aminopentyl)carbamate, 496 mg (1.757 mmol) 1-sulfanyl-3,6,9,12- tetraoxapentadecan-15-oic acid and 801 mg (2.108 mmol) HATU were dissolved in 5.95 ml DMF. The reaction mixture was cooled with an ice bath and 681 mg (920 jid, 5.272 mmol) N,N15 diisopropylethylamine was added. The mixture was stirred at room temperature for 4 h and storedovernight in a refrigerator at 4°C. The mixture was purified directly via preparative HPLC (eluent:acetonitrile/water + 0.1% TFA, gradient 20:80 - 80:20) followed by freeze-drying to give 255 mg (29%) of the target compound.LC-MS (Method 1): R1 = 0.87 mm; MS (Elpos): mlz = 467 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | C5-Boc - 4-carboxybenzenesulfonamide (120.8 mg, 0.6 mmol, 1.25 equiv.), EDC.HC1 (143.8 mg, 0.75 mmol, 1.6 equiv.) and HOBT.H20 (114.5 mg, 0.75 mmol, 1.6 equiv.)were dissolved in dry DMF (2.5 mL) under argon. After 5-10 minutes stuffing, N-Boc1,5-diaminopentane (0.1 mL, 0.48 mmol, 1 equiv.) and DIEA (260 tL, 1.5 mmol,3.1 equiv.) were added. Reaction mixture was stirred overnight at room temperature. Solvent was removed by rotary evaporation and the resulting sticky solid was taken up ina 1:1 mixture of EtOAc and saturated aqueous solution of NaHCO3. After decantation, the organic layer was washed with brine, dried over Na2504, filtered and concentrated. The crude was purified by automated silica gel flash column chromatography (5% MeOH in DCM) to give the desired compound as a white solid (173.8 mg, 0.45 mmol, 94%). ?HNMR (400MHz, MeOD) oe (ppm): 7.98-7.93 (m, 4H), 3.39 (t, I = 7.1 Hz, 2H), 3.05 (t, I= 6.9 Hz, 2H), 1.65 (quintet, I = 7.3 Hz, 2H), 1.56-1.49 (m, 2H), 1.42-1.38 (m, 9H + 2H).?3C-NMR (101 MHz, MeOD) oe (ppm): 168.71, 158.53, 147.53, 139.16, 128.90, 127.26, 79.80, 41.02, 30.03, 28.77, 25.18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | General procedure: tert-butyl(3-aminopropyl)carbamate (3a,508 mg, 2.93 mmol)was added toa stirred solutionof4-aminobenzoic acid (2a, 200 mg, 1.46 mmol), EDCI (421mg, 2.20 mmol), HOBt(237 mg, 1.76 mmol), DIEA (502 muL, 2.92 mmol) in DMF (10 mL), stirred overnight at RT. After monitored by TLC to observe completion of reaction, the mixture was diluted with water (20 mL), and then the water phase was extracted with ethylacetate (20 mL×2). The combined organic phase was washed with water (20 mL×3)for three times and dried with anhydrous Na2SO4. The crude product was purified bysilica gel column chromatography to afford intermediates 5aa in 81% yield as whitesolid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere; | General procedure: To a solution of 4-fluoroisobenzofuran-1,3-dione (300 mg, 1.09 mmol, 1 equiv) in 15 mL anhydrous 1,4-dioxane was added tert-butyl (2-aminoethyl)carbamate (226 mg,1.41 mmol 1.3 equiv). The solution was then stirred at 80 C for 12 h.After cooling to room temperature, the solution was extracted withAcOEt (50 mL×3). The organic layer was washed with H2O and brinefor 4 times, dried (MgSO4), concentrated and purified by silica gelcolumn chromatography (EA/PE) to afford the title compound 26 as alight yellow solid (199 mg, 0.48 mmol, 44% yield). |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; | To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (219 mg, 0.8 mmol, 1 eq.) in DMF (4 mL) were added DIPEA (264 pL, 1.6 mmol, 2 eq.) and tert-butyl (5-aminopropyl)carbamate (177 mg, 0.88 mmol, 1.1 eq.). The reaction mixture was heated to 90 C overnight. Cooled to room temperature, the mixture was diluted with EtOAc and EtOAc and washed with water and brine, dried over Na2S04 and concentrated in vacuo to obtain 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione that was used directly in next step.LCMS 458 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | A solution of <strong>[194853-86-6]4-fluoro-2-(trifluoromethyl)benzonitrile</strong> (7.00 g, 37.1 mmol), tert- butyl N-(5-aminopentyl)carbamate (10 g, 49.43 mmol), and Nu,Nu-diisopropylethyl amine (11 g, 85.11 mmol) in DMF (100 mL) stirred for 6 h at room temperature. The resulting solution was diluted with 400 mL of ethyl acetate, washed with 2x200mL brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography with silica gel (eluting with ethyl acetate/petroleum ether (1 : 1)) to give tert- butyl 5-(4-cyano-3-(trifluoromethyl)phenylamino)pentylcarbamate (11 g, 60%) as colorless oil. MS: (ESI, m/z): 372[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | i¥-(ter/-Butylcarbonyi)-i,5-diaminopenfane (44, 14.5 mg, 71.7 mipo, 2.00 equiv) was added to a suspension of 0~/er/-butyldip enylsily{-12-e ?i-l 7-oxo~19,20~ dihydrqpleurotmmlirt S40 [22 7 mg, 35.9 pmol, 1 equiv, dried by azeotropic distillation with benzene (200 mT)] and anhydrous magnesiu sulfate (21.5 mg, 179 mmol, 5.00 equiv) in dichoromethane (300 pL). The reaction was stirred for 4 h at 24 C. The resulting mixture was filtered through a small column of powdered sodium sulfate (0.5 cm x 0.5 cm). The column was rinsed with tliehloromeihane (5 0 ml) The filtrates were combined and the combined filtrates were concentrated to dryness. The residue obtained was transferred to a 4- niL vial with benzene (1.5 mL) and the resulting solution was concentrated to dryness. The reaction vessel was evacuated and refilled using a balloon of argon. This process was repeated twice. The residue obtained was dissolved in methanol (200 pL). Sodium cyanoborohydride (4.5 mg, 71.7 pmol, 2.00 equiv) and a solution of acetic acid (2.2 pL, 37.7 miho, 1 05 equiv) in methanol (100 m£) were added to the reaction vessel at 24 C. The reaction mixture was stirred for 4 It at 24 C. The product mixture was transferred to a separatory funnel that had been charged with dichloromethane (30 mL) and saturated aqueous sodium bicarbonate solution (2.0 mL) The layers that formed were separated and the aqueous layer was extracted with dichloromethane 5 mL). The organic layers were combined an dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue obtained was purified by automated flash-column chromatography (eluting with dichloromethane- 1 % ammonium hydroxide initially, grading to 1.0% methanol-dichloromethane-i % ammonium hydroxide, linear gradient) to afford the Secondary amine;45 as a colorless clear film (25.5 mg, 87%). Rr- 0 77 (10% methanol-dlchloromethane; UV, PAA CAM) 5H NMR. (400 MHz, CDC) d 7.68-7 62 (m, 4H, 2 x 1, 2 x i), 7.46-7.35 5.53 J 8 0 Hz, IH, Hh>, 4.71 (hr s, IH, NH)S 4.14 (dd, J - 19.2, 2.4 Hz, 2H, B32), 3.65 (d I == 5.6 Hz, IH, Hu), 3.14 -2.70 ( 2.44 (br , 1H, Hi ). 2.28 (dd, J - 19.2, 10.8 Hz, JH, 1 x ), 2.20-2.1 1 (m, IH, 1 x M2), 2,04-1.94 (m, 2H, 1 x H4I 1 x HJ3)> 1-78 (d, J = 14.4 Hz, IH, 1 x ), 1.73 1.61 (m, 3H, 2 x 1 x H?), 1.61-1.46 (m, 6H, 1 x , 1 k H-, 2 x HlS>, 2 x H.), 1.42 (s, 9H, <>), 1.39-1.31 (m, 7H, 3 x Hi3, 2 x e, 2 x H35), 1.14 (td, J - 13 6, 2.8 Hz, IH, 1 x H8), 1.07 (s, 9H, H24), 1.01 (s, 3H, Hi), 0.88-0.77 (m, 4H, 1 x H}3, 3 x >), 0.61 (d, J - 6.8 Hz, 3H, CDCh'i d 216.3 iC>, 170 0 (C), 156.1 (C), 135.5 (CH), 132 7 (C), 132,6 (C), 130 0 (CH), 127.8 (CH), 127.8 (CH), 79.2 (C), 72.0 (CH), 68.8 (CH), 62.9 (?}, 58.3 (CH), 48.4 (?}, 48.2 (CH,), 44.4 (C), 41 .9 (C), 43.5 (CH2), 40.2 (C), 39.8 (CH2), 39.1 (CH), 36.6 (CH), 34.4 (C), 33.3 (C%), 30.6 (CII 29.5 (CH2), 28.4 (CH3), 26.9 (C), 26.7 (1 x C, 1 x C), 25.5 (CH2), 23.9 (CH2), 19.2 (C), 19.1 (C), 16.7 (CHj), 14.9 (C), 7.9 (<%). IR (AIR- FUR), cm" 1: 3381 (br w), 2947 (w), 1733 (m), 1 73 (s), 1465 (w), 1429 (w), 1199 (s), 1134 (s), 1098 (m), 1023 (s), 966 (w), 837 (m), 799 (m), 722 (s). HRMS-ESI ( /z): [M f H] * ealcd for GtHnNjOrSi, 819.5344; found, 819.5352. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.3% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In dichloromethane; at 20℃; for 8h;Inert atmosphere; | A 10-mL flask was chargedwith 5 (162 mg, 0.5 mmol, 1 equiv.), Et3N (151.5 mg, 4.5 mmol, 3 equiv.), HOBT (33.7 mg, 0.25 mmol,0.5 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (143.2 mg, 0.75 mmol, 1.5 equiv.)and tert-butyl (5-aminopentyl)carbamate (101 mg, 0.5 mmol, 1.0 equiv.) under nitrogen atmosphere.After dissolution in 5 mL of anhydrous dichloromethane (DCM), the mixture was stirred at roomtemperature for 8 h. The organic phase was washed three times with water and dried over anhydrousMgSO4. The residue was purified by flash chromatography (petroleum ether:EtOAc = 1:1) to giveproduct 6. Colorless oil. Yield: 133 mg, 52.3%. 1H NMR (600 MHz, CDCl3) delta 7.43 (s, 2H), 5.80 (brs,1H, NH), 3.86 (s, 3H), 3.43 (s, 2H), 3.24-3.21 (m, 2H), 3.12-3.08 (m, 2H), 1.52-1.47 (m, 4H), 1.43 (s, 9H),1.33-1.29 (m, 2H). 13C NMR (150 MHz, CDCl3) delta 169.7, 156.3, 153.4, 133.9, 133.5, 118.4, 79.3, 60.7, 42.2,40.3, 39.8, 29.9, 29.1, 28.6, 24.0. ESI-MS m/z 540.9 [M + Cl]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Under an argon atmosphere, to a solution of tert-butyl N-(5-aminopentyl)carbamate (300 mg, 1.46 mmol) in dichloromethane (15 mL) were added triethylamine (0.206 mL, 1.48 mmol) and 1-amidinopyrazole hydrochloride (217 mg, 1.46 mmol). After stirring at room temperature overnight, the mixture was purified by reversed-phase HPLC (0.05% (v/v)-containing TFA, water/acetonitrile) to give the title compound (408 mg, yield quantitative). 1H-NMR (400 MHz, Deuterium Oxide) delta3.10 (t, J=7.0 Hz, 2H), 2.99 (t, J=6.7 Hz, 2H), 1.56-1.47 (m, 2H), 1.46-1.37 (m, 2H), 1.35 (s, 9H), 1.32-1.23 (m, 2H). MS (ESI)m/z: 245 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a solution of 3-(1H-indol-3-yl)propanoic acid (8) (1.00 g, 5.29 mmol) in DMF (30 mL) was added EDC·HCl (1.52 g, 7.93 mmol) and HOBt·H2O (1.21 g, 7.93 mmol). The resulting mixture was stirred at room temperature for 30 minutes. A solution of the amine 21 (1.18 g, 5.82 mmol) in DMF (10 mL) and TEA (2.00 mL, 14.3 mmol) was added and the reaction was stirred for 16 hours at room temperature. The DMF was evaporated and the residue was partitioned with EtOAc (150 mL) and water (150 mL). The layers were separated and the organic solution was washed with 1N NaHSO4 (150 mL), saturated NaHCO3 (150 mL) and brine (150 mL). The organic layer was then dried (Na2SO4), filtered and concentrated to afford 1.99 g (100% yield) of compound 22 as a tan foam: 1H NMR (400 MHz, CDCl3) delta 9.06 (bs, 1H), 7.58 (d, J = 7.80 Hz, 1H), 7.38 (d, J = 7.80 Hz, 1H), 7.17 (dt, J = 6.90, 1.00 Hz, 1H), 7.09 (dt, J = 7.80, 0.90 Hz, 1H), 7.00 (d, J = 2.30 Hz, 1H), 5.34 (bs, 1H), 4.62 (bs, 1H), 3.07- 3.13 (m, 4H), 3.02 (apparent q, J ~ 6.75 Hz, 2H), 2.54 (t, J = 7.30 Hz, 2H), 1.46 (s, 9H), 1.33 (quint, J = 7.30 Hz, 2H), 1.20- 1.26 (m, 2H), 0.93- 1.01 (m, 2H). 13C NMR (100 MHz, CDCl3) delta 173.05, 156.49, 136.67, 127.02, 122.42, 121.86, 119.17, 118.60, 114.21, 111.57, 79.57, 40.50, 39.16, 37.59, 30.05, 29.15, 28.55, 23.70, 21.72. LCMS (40-95% acetonitrile in 0.05% TFA over 10 minutes) retention time = 4.12 minutes, ESI m/z = 374, [M+H]+ . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With trimethylamine; In dichloromethane; at 20℃; for 2h; | A solution of Boc-l ,5-diaminopentane (0.050 g, 0.25 mmol) and trimethylamine (0.1 mL, 0.72 mmol) in CH2CI2 (2 mL) was added dropwise to a solution of <strong>[68528-80-3]suberic acid bis-(N-hydroxysuccinimide ester)</strong> (DSS, 0.23 g, 0.62 mmol) in 3 mL CH2CI2, under mild stirring at room temperature. After 2 h, the solvent was evaporated. The crude material was purified on a silica column using a gradient from CH2CI2 to CH2CI2/CH3CN 1 : 1 to afford 0.072 g (64%) of compound 13. ESI-Mass calcd for C22H38N3O7 [M+H]+ 456.3, found 456.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 12h;Inert atmosphere; | General procedure: To a 200-mL (24/40) round-bottomed flask equippedwith a magnetic stir bar was added 2 (2.05 g, 11.8 mmol), 2.1 mL(12 mmol) of DIPEA, and 55 mL of MeCN. While stirring at roomtemperature, tert-butyl(3-aminopropyl)carbamate (2.05 g, 11.8 mmol)was added and the solution was stirred for 12 h. The solution wasinitially colorless and white precipitate began to form after a few hours.The precipitate was filtered off and rinsed with water (30 mL) and driedunder nitrogen to afford 3.12 g (10.1 mmol, 86%) of 3a as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | General procedure: tert-butyl(3-aminopropyl)carbamate (3a,508 mg, 2.93 mmol)was added toa stirred solutionof4-aminobenzoic acid (2a, 200 mg, 1.46 mmol), EDCI (421mg, 2.20 mmol), HOBt(237 mg, 1.76 mmol), DIEA (502 muL, 2.92 mmol) in DMF (10 mL), stirred overnight at RT. After monitored by TLC to observe completion of reaction, the mixture was diluted with water (20 mL), and then the water phase was extracted with ethylacetate (20 mL×2). The combined organic phase was washed with water (20 mL×3)for three times and dried with anhydrous Na2SO4. The crude product was purified bysilica gel column chromatography to afford intermediates 5aa in 81% yield as whitesolid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: toluene / 3 h / Reflux 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 16 h / 0 - 20 °C 3.1: hydrazine hydrate / ethanol / 1 h / Reflux | ||
Multi-step reaction with 3 steps 1: triethylamine / toluene / 48 h / Inert atmosphere; Reflux 2: lithium hexamethyldisilazane / tetrahydrofuran / 8 h / 0 - 20 °C / Inert atmosphere 3: hydrazine / ethanol / Inert atmosphere; Reflux | ||
Multi-step reaction with 3 steps 1: triethylamine / toluene / 72 h / 110 °C / Inert atmosphere 2: lithium hexamethyldisilazane / tetrahydrofuran / 8 h / 0 - 20 °C 3: hydrazine / ethanol / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of intermediate 2 (0.07 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was stirred for 1 h at 20 C. The solvent was evaporated, and the crude material triturated with tert-butyl methyl ether and filtered to afford the ssc-Pix5 (a mixture of regioisomers) as a solid (71%). 1H NMR (300 MHz, CD3OD, regioisomers): delta 9.22 (1H, bs), 9.00-8.93 (1H, bs), 7.92 (1H, bs), 7.37-7.30 (1H, m), 7.20 (1H, bs), 3.35-3.30 (2H), 3.01 (2H, t, J 7.5 Hz), 1.81-1.76 (4H, m), 1.61-1.59 (2H, m). 13C NMR (75 MHz, CD3OD, regioisomers): delta 184.03, 182.89, 182.01, 181.98, 156.47, 153.00, 155.54, 154.99, 149.98, 149.67, 141.18, 140.00, 128.73, 128.33, 127.99, 127.52, 122.98, 122.52, 119.99, 119.47, 111.63, 111.12, 43.52, 40.66, 29.60, 28.35, 25.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 50℃; for 18h; | A solution of <strong>[144511-13-7]6,9-difluorobenzo[g]isoquinoline-5,10-dione</strong>20 (0.04 mmol), diisopropylethylamine (0.06 mmol) and tert-butyl 5- aminopentylcarbamate (0.05 mmol) in dry dioxane (1.5 mL) was stirred at 50 C for 18 h. The crude material was purified using column chromatography eluting with 1% methanol/dichloromethane to give intermediate 2 (a mixture of regioisomers) as a solid (68%). 1H NMR (300 MHz, CDCl3, regioisomers): delta 10.02 (1H, bs), 9.54 and 9.48 (1H, bs), 9.02 (1H, bs,), 8.04-8.02 and 8.00-7.99 (1H, m), 7.42-7.33 (1H, m), 7.17-7.10 (1H, m), 4.58 (1H, bs), 3.40-3.34 (2H, m), 3.19-3.13 (2H, m), 1.58-1.52 (6H, m), 1.44 (9H, bs). 13C NMR (75 MHz, CDCl3, regioisomers): delta 183.32, 182.55, 181.46, 156.01, 154.95, 151.47, 154.95, 154.74, 149.43, 149.25, 139.57, 138.25, 127.54, 127.19, 126.80, 126.46, 121.09, 120.55, 118.50, 118.32, 110.92, 110.51, 79.21, 42.97, 40.34, 29.85, 28.72, 24.26, 24.42. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of 2-(4-((5-(((5-(ter/-butyl)oxazol-2-yl)methyl)thio)thiazol-2- yl)carbamoyl)piperidin-l-yl)acetic acid (300 mg, 0.68 mmol) in DMF (10 mL) was added tert- butyl (5-aminopentyl)carbamate (166 mg, 0.82 mmol) and DIEA (196 mg, 1.36 mmol), followed by HOBt (137 mg, 1.02 mmol) and EDCFHCl (196 mg, 1.02 mmol). The mixture was stirred at RT overnight then diluted with H2O and extracted with EA. The combined organic layers were washed with saturated NaElCCb, dried over Na2S04, filtered and concentrated to give the crude product, which was purified using silica gel eluting with DCM/MeOH (0% to 10%) to give tert- butyl (5-(2-(4-((5-(((5-(/c77-butyl )oxazol-2-yl (methyl )thio)thiazol-2-yl (carbamoyl )pi peri din- 1 _ yl)acetamido)pentyl)carbamate (409 mg, 96% yield) as a solid. MS (ESI) m/z 623.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: 2-(6-bromo-1H-indol-3-yl)acetic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 0.5h; Stage #2: 5-tert-butoxycarbonylamino-1-aminopentane In dichloromethane at 20℃; for 1.5h; Stage #3: With trifluoroacetic acid In dichloromethane at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1165 mg | With triethylamine In dichloromethane at 0 - 20℃; for 2h; | 5.1 Step 1: tert-Butyl (5-(4-methyl-3-nitrophenylsulfonamido)pentyl)carbamate A solution of N-Boc-cadaverine (650 mg, 3.12 mmol) and TEA (0.900 mL, 6.39 mmol) in DCM (25 mL) was cooled at 0 °C, to which a solution of 4-methyl-3-nitrobenzenesulfonyl chloride (795 mg, 3.27 mmol) in DCM (50 mL) was added dropwise. The reaction was allowed to warm to RT and stirred at RT for 2 h. The RM was partially concentrated under reduced pressure and washed with water (×3), dried over magnesium sulfate, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography eluting with EtOAc in CHX (from 0% to 100%) to afford the title compound (1165 mg). Method LCMS1: Rt = 1.09 min; [M+H]+ = 402.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridine at 90℃; for 2h; Inert atmosphere; | tert-Butyl N-{5-[(4-fluoro-9,10-dioxo-9,10-dihydroanthracen-1-yl)amino]pentyl}carbamate 54 1,4-Difluoro-9,10-dihydroanthracene-9,10-dione (0.15 mmol) was dissolved in dry pyridine (3 mL) to which tert-butyl N-(5-aminopentyl)carbamate (0.15 mmol) was added. The reaction mixture was stirred at 90 oC for 2 h under inert atmosphere. The reaction mixture was then concentrated under vacuum and purified using preparative TLC plates (silica; 5% methanol in dichloromethane) to afford 54 as a red solid (89%). δH (300 MHz, CDCl3) 9.91 (1 H, bs, NH), 8.25 - 8.20 (2 H, m, 2 x Aryl CH), 7.77 - 7.68 (2 H, m, 2 x Aryl CH), 7.34 - 7.26 (1 H, m, Aryl CH), 7.07 - 7.02 (1 H, m, Aryl CH), 4.60 (1 H, bs, NH), 3.31 (2 H, q, J 6.3, CH2), 3.16 (2 H, q, J 6.2, CH2), 1.78 (2 H, quin, J 7.0, CH2), 1.58 - 1.53 (4 H, m, 2 x CH2), 1.44 (9 H, bs, Boc). δC (75 MHz, CDCl3) 184.44 and 182.33 (2 x CO), 156.02 (Boc CO) 154.94 and 151.48 (Aryl CF), 149.01 (Aryl CNH), 134.28, 133.48, 120.14 and 111.26 (4 x Aryl C), 133.72, 133.08, 126.61, 126.44, 126.01 and 119.80 (6 x Aryl CH), 42.92, 40.37, 29.85, 29.68 and 24.31 (5 x CH2), 28.42 (Boc CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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 at 20℃; | 1 Example 1 (Method 1): Synthesis of 4-[2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2S)-3-methyl-1-(propane-2-sulfonyl)butan-2-yl]-2-oxopiperidin-3-yl]acetamido]-N-[7-[(4-[2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2S)-3-methyl-1-(propane-2-sulfonyl)butan-2-yl]-2-oxopiperidin-3-yl] acetamido] phenyl)formamido] heptyl]benzamide (I-8) To a stirred solution of 4-amino-N-[7-[(4-aminophenyl)formamido]heptyl] benzamide (30 mg, 0.081 mmol, Intermediate Y) and [(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2S)-3-methyl-1-(propane-2-sulfonyl)butan-2-yl]-2-oxopiperidin-3-yl]acetic acid (93 mg, 0.16 mmol, Intermediate AJ) in DMF (2 mL) were added DIEA (42 mg, 0.33 mmol) and HATU (43 mg, 0.12 mmol) at room temperature. The resulting mixture was stirred for overnight at rt and then purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 um ; Mobile Phase A: Water (plus 10 mmol/L FA); Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 65% B to 85% B in 7 min; Detector: UV 254/220 nm; Desired fractions were collected at 6.3 min) and concentrated under reduced pressure and lyophilized to afford title compound (7.9 mg, 7%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.91-7.76 (m, 8H), 7.30-7.20 (m, 8H), 7.11-7.00 (m, 4H), 6.88-6.84 (m, 4H), 5.12 (d, J= 11.0 Hz, 2H), 4.03 (dd, J= 13.9, 10.5 Hz, 2H), 3.56-3.46 (m, 2H), 3.41-3.32 (m, 6H), 3.18-3.09 (m, 2H), 3.07 (d, J= 13.3 Hz, 2H), 2.63 (d, J = 13.3 Hz, 2H), 2,34 (t, J= 13.7 Hz, 2H), 2.25-2.21 (m, 2H), 2.16 (dd, J = 13.7, 3.1 Hz, 2H), 1.67-1.64 (m, 4H), 1.51-1.25 (m, 26H), 0.70 (d, J= 6.6 Hz, 6H), 0.58 (d, J= 6.9 Hz, 6H); LC/MS (ESI, m/z): [(M + 1)]+ = 1468.9. | |
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 at 20℃; | 1 Example 1 (Method 1): Synthesis of 4-[2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2S)-3-methyl-1-(propane-2-sulfonyl)butan-2-yl]-2-oxopiperidin-3-yl]acetamido]-N-[7-[(4-[2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2S)-3-methyl-1-(propane-2-sulfonyl)butan-2-yl]-2-oxopiperidin-3-yl] acetamido] phenyl)formamido] heptyl]benzamide (I-8) To a stirred solution of 4-amino-N-[7-[(4-aminophenyl)formamido]heptyl] benzamide (30 mg, 0.081 mmol, Intermediate Y) and [(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2S)-3-methyl-1-(propane-2-sulfonyl)butan-2-yl]-2-oxopiperidin-3-yl]acetic acid (93 mg, 0.16 mmol, Intermediate AJ) in DMF (2 mL) were added DIEA (42 mg, 0.33 mmol) and HATU (43 mg, 0.12 mmol) at room temperature. The resulting mixture was stirred for overnight at rt and then purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 um ; Mobile Phase A: Water (plus 10 mmol/L FA); Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 65% B to 85% B in 7 min; Detector: UV 254/220 nm; Desired fractions were collected at 6.3 min) and concentrated under reduced pressure and lyophilized to afford title compound (7.9 mg, 7%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.91-7.76 (m, 8H), 7.30-7.20 (m, 8H), 7.11-7.00 (m, 4H), 6.88-6.84 (m, 4H), 5.12 (d, J= 11.0 Hz, 2H), 4.03 (dd, J= 13.9, 10.5 Hz, 2H), 3.56-3.46 (m, 2H), 3.41-3.32 (m, 6H), 3.18-3.09 (m, 2H), 3.07 (d, J= 13.3 Hz, 2H), 2.63 (d, J = 13.3 Hz, 2H), 2,34 (t, J= 13.7 Hz, 2H), 2.25-2.21 (m, 2H), 2.16 (dd, J = 13.7, 3.1 Hz, 2H), 1.67-1.64 (m, 4H), 1.51-1.25 (m, 26H), 0.70 (d, J= 6.6 Hz, 6H), 0.58 (d, J= 6.9 Hz, 6H); LC/MS (ESI, m/z): [(M + 1)]+ = 1468.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium carbonate In dimethyl sulfoxide at 70℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)acetic acid; 5-tert-butoxycarbonylamino-1-aminopentane 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 dimethyl sulfoxide at 20℃; for 4h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 6h; | 4.1.24. N-(2-aminoethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide (19a) General procedure: To a solution of compound 18 (54 mg, 0.16 mmol) in DMSO (10 mL)were added N-Boc-ethylenediamine (31 mg, 0.192 mmol), HATU (80mg, 0.208 mmol), and DIPEA (110 μL, 0.65 mmol) at room temperature.After stirring for 4 h, the solution was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous Na2SO4 andconcentrated. The crude product was purified by silica gel columnchromatography to obtain yellow solid (70 mg, 90% yield). 1H NMR(400 MHz, CDCl3) δ 8.32 (s, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.24 (d, J =7.1 Hz, 1H), 7.14 (s, 1H), 6.83 (d, J = 8.5 Hz, 1H), 4.97 (dd, J = 11.8,5.0 Hz, 1H), 3.98 (s, 2H), 3.45-3.35 (m, 2H), 3.25 (t, J = 5.3 Hz, 2H),2.96-2.89 (m, 1H), 2.87-2.73 (m, 2H), 2.66 (s, 2H), 2.19-2.13 (m, 1H),1.41 (s, 9H). ESI-MS: m/z 496.35 [M+Na]+. This yellow solid was dissolvedin DCM, 1 mL TFA was added at room temperature. After stirringfor 6 h, then the solution was evaporated under vacuum to obtain thecrude compound 19a, which was used without further purification. ESIMS:m/z 373.76 [M+H]+. |
72% | Stage #1: 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)acetic acid; 5-tert-butoxycarbonylamino-1-aminopentane 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 dimethyl sulfoxide at 20℃; for 4h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 6h; | 4.1.24. N-(2-aminoethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide (19a) General procedure: To a solution of compound 18 (54 mg, 0.16 mmol) in DMSO (10 mL)were added N-Boc-ethylenediamine (31 mg, 0.192 mmol), HATU (80mg, 0.208 mmol), and DIPEA (110 μL, 0.65 mmol) at room temperature.After stirring for 4 h, the solution was diluted with water, extracted withethyl acetate, washed with brine, dried over anhydrous Na2SO4 andconcentrated. The crude product was purified by silica gel columnchromatography to obtain yellow solid (70 mg, 90% yield). 1H NMR(400 MHz, CDCl3) δ 8.32 (s, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.24 (d, J =7.1 Hz, 1H), 7.14 (s, 1H), 6.83 (d, J = 8.5 Hz, 1H), 4.97 (dd, J = 11.8,5.0 Hz, 1H), 3.98 (s, 2H), 3.45-3.35 (m, 2H), 3.25 (t, J = 5.3 Hz, 2H),2.96-2.89 (m, 1H), 2.87-2.73 (m, 2H), 2.66 (s, 2H), 2.19-2.13 (m, 1H),1.41 (s, 9H). ESI-MS: m/z 496.35 [M+Na]+. This yellow solid was dissolvedin DCM, 1 mL TFA was added at room temperature. After stirringfor 6 h, then the solution was evaporated under vacuum to obtain thecrude compound 19a, which was used without further purification. ESIMS:m/z 373.76 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95 % | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 3 tert-butyl (5-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3- methylpyridin-2-yl)benzamido)pentyl)carbamate (4c): Lumacaftor (3-(6-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoic acid) (181 mg, 0.40 mmol), tert-butyl (5-aminopentyl)carbamate (121 mg, 0.60 mmol), DIEA (350 µL, 2.00 mmol), and HOBt (54 mg, 0.4mmol) were dissolved in DCM (6 mL), followed by addition of EDCI HCl (153 mg, 0.50 mmol). The reaction was stirred at rt for 16 hours before water was added, the mixture partitioned, and the aqueous layer extracted with DCM twice. The combined organic extracts were washed with brine, dried over Na2SO4, concentrated, and the resulting crude oil was purified by silica gel chromatography (0-50% EtOAc/Hex) to obtain 4c as an oil (240 mg, 0.38 mmol, 95%). LC/MS [M+H]+ m/z calc.637.28, found 637.3.1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.80 (dt, J = 7.6, 1.6 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.57 (dt, J = 7.7, 1.5 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.27 (dd, J = 8.1, 1.8 Hz, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.25 (s, 1H), 3.17 (d, J = 6.8 Hz, 2H), 4.61 (s, 1H), 3.49 (q, J = 7.0, 6.8, 6.3 Hz, 2H), 2.29 (s, 3H), 1.79 (q, J = 3.9 Hz, 2H), 1.56 (q, J = 7.2 Hz, 2H), 1.46 (s, 11H), 1.36 - 1.27 (m, 2H), 1.20 (q, J = 3.9 Hz, 2H), 0.97 - 0.89 (m, 2H). |
95 % | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 3 tert-butyl (5-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3- methylpyridin-2-yl)benzamido)pentyl)carbamate (4c): Lumacaftor (3-(6-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoic acid) (181 mg, 0.40 mmol), tert-butyl (5-aminopentyl)carbamate (121 mg, 0.60 mmol), DIEA (350 µL, 2.00 mmol), and HOBt (54 mg, 0.4mmol) were dissolved in DCM (6 mL), followed by addition of EDCI HCl (153 mg, 0.50 mmol). The reaction was stirred at rt for 16 hours before water was added, the mixture partitioned, and the aqueous layer extracted with DCM twice. The combined organic extracts were washed with brine, dried over Na2SO4, concentrated, and the resulting crude oil was purified by silica gel chromatography (0-50% EtOAc/Hex) to obtain 4c as an oil (240 mg, 0.38 mmol, 95%). LC/MS [M+H]+ m/z calc.637.28, found 637.3.1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.80 (dt, J = 7.6, 1.6 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.57 (dt, J = 7.7, 1.5 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.27 (dd, J = 8.1, 1.8 Hz, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.25 (s, 1H), 3.17 (d, J = 6.8 Hz, 2H), 4.61 (s, 1H), 3.49 (q, J = 7.0, 6.8, 6.3 Hz, 2H), 2.29 (s, 3H), 1.79 (q, J = 3.9 Hz, 2H), 1.56 (q, J = 7.2 Hz, 2H), 1.46 (s, 11H), 1.36 - 1.27 (m, 2H), 1.20 (q, J = 3.9 Hz, 2H), 0.97 - 0.89 (m, 2H). |
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. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
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. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
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P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
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P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
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. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
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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. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
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P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
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P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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