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CAS No. : | 55750-61-3 | MDL No. : | MFCD00133523 |
Formula : | C10H8N2O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | TYKASZBHFXBROF-UHFFFAOYSA-N |
M.W : | 252.18 | Pubchem ID : | 3299229 |
Synonyms : |
AMAS
|
Chemical Name : | 2,5-Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate |
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.3 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 61.19 |
TPSA : | 101.06 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.89 cm/s |
Log Po/w (iLOGP) : | 1.12 |
Log Po/w (XLOGP3) : | -1.48 |
Log Po/w (WLOGP) : | -2.24 |
Log Po/w (MLOGP) : | -0.8 |
Log Po/w (SILICOS-IT) : | -0.81 |
Consensus Log Po/w : | -0.84 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.21 |
Solubility : | 157.0 mg/ml ; 0.621 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.14 |
Solubility : | 184.0 mg/ml ; 0.728 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.04 |
Solubility : | 278.0 mg/ml ; 1.1 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.88 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
116 g | With triethylamine In dichloromethane at 20℃; for 2 h; | To a 500 ml three-necked flask, N-maleimidyl acetic acid (94 g, 0.6 mol)And dichloromethane 300ml,Oxalyl chloride (90 g, 0.72 mol) was then added,The reaction was warmed to reflux, a large amount of gas was released.After 2h the reaction became clear,Concentrate to remove methylene chloride and excess oxalyl chloride,Addition of 200 ml of methylene chloride to remove the residual acid in one pass afforded crude N-maleimidoacetyl chloride.The crude product was dissolved in 200 ml of dichloromethane,Was added dropwise to N-hydroxysuccinimide (69 g, 0.6 mol)Triethylamine (80.8 g, 0.8 mol)Dissolved in 300 ml of dichloromethane,Ice water cooling control temperature does not exceed 20 , drip finished room temperature 2h.The reaction solution was washed with 200 ml of water to remove triethylamine hydrochloride,1N hydrochloric acid 100ml washing to remove excess triethylamine,200ml saturated salt water, washed and dried,Concentrated to dry off like white solid 137g,After recrystallization from a mixed solvent of ethyl acetate and petroleum ether, 116 g of a white solid was obtained,HPLC purity 98.7percent, 76.7percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3 N-palmitoyl-PEG3,400 amine trifluoroacetate (350 mg, 0.0925 mM) was dissolved in 3.5 mL tetrahydrofuran and diisopropylethylamine (40 mL) was added to adjust the pH to about 8.0 (as measured with a moistened indicator paper). After about 10 minutes of stirring, maleimido acetic acid N-hydroxysuccinamide ester (48 mg, 0.185 mM) (Molecular Biosciences, Lot 11158) was added and the mixture was stirred for about an additional four hours. The addition of diethyl ether (90 mL) resulted in the precipitation of a white solid that was isolated and dried under reduced pressure to yield 330 mg of N-Maleimidoacetyl-N'-palmitoyl-PEG3,400 (MH+ 3806.89 (cluster)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1.5h; | To a solution of (2-methyl-4-(4-rnethylpiperazin-1-yl)-1 OHbenzo[b]thieno[2,3-e][1 ,4]diazepin-7-yl)rnethanamine, prepared as described inExample 3, (3.5 mg, 102 Jrnoles) in 185 JL of DMF and 4.5 pl of tributylarnine wasadded 260 pl of a DMF solution of N-(a-rnaleimidoacetoxy) succinimide ester(AMAS, 10 mg/ml, 2.6 mg, 10.2 pmoles). The resulting solution was allowed to stirfor 90 minutes at 20 C, then used as such in conjugation reaction with thiol-activatedprotein. | |
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1.5h; | To a solution of (2-methyl-4-(4-methylpiperazin-1-yl)- 10H-benzo[h]thieno[2,3-e][1,4]diazepin-7-yl)methanamine, prepared as described in Example 3, (3.5 mg, 10.2, mumoles) in 185 muL of DMF and 4.5 muL of tributylamine was added 260 muL of a DMF solution of N-(alpha-maleimidoacetoxy)succinimide ester (AMAS, 10 mg/mL, 2.6 mg, 10.2 mumoles). The resulting solution was allowed to stir for 90 minutes at 20 C, then used as such in conjugation reaction with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a solution of ( 1-rnethyl-4-(2-rnethyl-1 OH-benzo[b]thieno[2,3-e][1 ,4]diazepin-4-yl)piperazin-2-yl)rnethanarnine, prepared as described in Example1, (1 0.3 mg, 30.2 t-Jmoles) in 570 f.JL of DMF and 13.3 iJL of tributylamine was added760 iJL of a DMF solution of N-(o-maleirnidoacetoxy) succinimide ester (AMAS, 10rng/ml, 7.6 mg, 30.2 iJmoles). The resulting solution was allowed to stir for 18 hoursat 20 C, then used as such in conjugation reactions with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of 3-(2-(4-(6-(2-aminoethoxy)benzo[d]isoxazol-3-yl)piperidin-l-yl)ethyl)- 9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[ 1 ,2-a]pyrirnidin-4-one, prepared as described in Example 1, (4.0 mg, 8.5 tmoles) in 215 muIota_ of DMF and 4.3 iiL of tributylamine was added 214 iL of a DMF solution of N-(a-maleimidoacetoxy) succinimide ester (AM AS, 10 mg/niL, 2.1 mg, 8.5 umoies). The resulting solution was allowed to stir for 60 minutes at 20 C, then used as such in conjugation reaction with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1.5h; | To a solution of 3-(2-(4-(6-(2-aminoethoxy)benzo[d]isoxazol-3-yi)piperidin- 1 -yl)ethyi)- 2-methyl-6J,8,9 etrahydro-4H-pyrido[l,2-a]pyrimidin-4-one, prepared as described in Example 3, (3.4 mg, 7.58 imoles) in 185 L of DMF and 3.7 uL of tributylamine was added 190 ,uL of a DMF solution of N-(a-maleimidoaeetoxy) suecinimide ester (AMAS, 10 mg/mL, 1.9 mg, 7.58 mu iotaomicronomicronbeta). The resulting solution was allowed to stir for 90 minutes at 20 C, then used as such in conjugation reaction with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1.5h; | Example 6 N-((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methyl)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamide To a solution of Example 1 (MW 477.4 2.2 mg, 4.61 iimoles) in 1 10 muEpsilon of DMF and 2.3 uL of tributylamine was added 1 16 iiL of a DMF solution of N-(a-maleiniidoacetoxy) succinimide ester (AMAS, MW 252.2, 10 mg/mL, 1.16 mg, 4.61 mupiiotaomicronepsilonbeta). The resulting solution was allowed to stir for 90 minutes at 20 C, and then used as such in conjugation reaction with thiol- activated protein. | |
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1.5h; | Example 6 N-((7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)methyl)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamide (0232) (0233) To a solution of Example 1 (MW 477.4 2.2 mg, 4.61 mumoles) in 110 muL of DMF and 2.3 muL of tributylamine was added 116 muL of a DMF solution of N-alpha-maleimidoacetoxy)succinimide ester (AMAS, MW 252.2, 10 mg/mL, 1.16 mg, 4.61 mumoles). The resulting solution was allowed to stir for 90 minutes at 20 C., and then used as such in conjugation reaction with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a solution of (1-methyl-4-(2-methyl- 10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-2-yl)methanamine, prepared as described in Example 1, (10.3 mg, 30.2 mumoles) in 570, muL of DMF and 13.3 muL of tributylamine was added 760 muL of a DMF solution of N-(alpha-maleimidoacetoxy)succinimide ester (AMAS, 10 mg/mL, 7.6 mg, 30.2 mumoles). The resulting solution was allowed to stir for 18 hours at 20 "C, then used as such in conjugation reactions with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of 2-(2-(2-(aminomethyl)-4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol, prepared as described in Example 1, (7 .8 mg, 19.0 mumoles) in 410 muL of DMF and 8.9 muL of tributylamine was added 480 muL of a DMF solution of N-(alpha-maleimidoacetoxy)succinimide ester (AMAS, 10 mg/mL, 4.8 mg, 19.0 mumoles). The resulting solution was allowed to stir for 60 minutes at 20 C, then used as such in conjugation reaction with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of 2-{2-[ 4-(3-aminomcthyl-dibenzo[b,f][1,4]thiazepin-11-yl)-piperazin-1-yl]-ethoxy}-ethanol, prepared as described in Example 3, (5.6 mg, 13.6 mumoles) in 295 muL of DMF and 6.4 muL of tributylamine was added 340 muL of a DMF solution of N-(alpha-maleimidoacetoxy)succinimide ester (AMAS, 10 mg/mL, 3A- mg, 13.6 mumoles). The resulting solution was allowed to stir for 60 minutes at 20 C, then used as such in conjugation reaction with thiol-activated protein. | |
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of 2-{2-[4-(3-aminomethyl-dibenzo[b,f][1,4]thiazepin-11-yl)-piperazin-1-yl]-ethoxy}-ethanol, prepared as described in Example 3, (5.6 mg, 13.6 mumoles) in 295 muL of DMF and 6.4 muL of tributylamine was added 340 muL of a DMF solution of N-(alpha-maleimidoacetoxy)succinimide ester (AMAS, 10 mg/mL, 3.4 mg, 13.6 mumoles). The resulting solution was allowed to stir for 60 minutes at 20 C., then used as such in conjugation reaction with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | General procedure: resin loading. In a 20 mL solid phase reaction vessel (plastic syringe with PET frit)added 1 g of 2-chlorotrityl chloride resin (1 mmol based on the manufacturer?s label), followed by a solution of Fmoc-Dpr(ivDde)-OH or Fmoc-Lys(ivDde)-OH (1.5 mmol, 1.5 equiv), and DIEA (1 mmol, 1 equiv) in 10 mL of dry CH2C12/DMF, 1/1, v/v. The vessel was shaken formm, and then more DIEA (1.5 mmol, 1.5 equiv) was added. The mixture was shaken for additional 2 hours at RT. Methanol (2.5 mL) was added to quench unreacted sites. After 30 mm, resin was washed with DMF (5 x 10 mL), CH2C12 (5 x 10 mL), ethyl ether (5 x 10 mL), and dried in vacuo.[0351] Loading was determined by treating the small amount of resin (2-4 mg) with 20% piperidine/DMF (2 mL) for 2 hours in volumetric flask (10 or 20 mL). Volume was adjusted with DMF; absorption at 301 nm was measured. Loading was calculated by the following equation:Loading (mmol/g) = (flask volume x A301)/(7 800 x mg) x 1000Average loading was 0.6 mmol/g Fmoc removal step. Resin containing Fmoc-protected peptide was treated with 20% piperidine in DMF (10 mL per gram of resin) for 2 h at room temperature. Then the resin was washed with DMF (5 x 1 mL per gram of resin), CH2C12 (5 x 1 mL per gram of resin), ethyl ether (5 x 1 mL per gram of resin), and dried in vacuo Coupling step. To the resin (1 equiv) containing deprotected N-terminus amino acid (AA), a solution of Fmoc-AA-OH (2 equiv), HATU (2 equiv), and DIEA (4 equiv) in DMF (1 mL per gram of resin) was added. The reaction vessel was agitated for 3-4 h. Then the resin was washed with DMF (5 x 1 mL per gram of resin), CH2C12 (5 x 1 mL per gram of resin), ethyl ether (5 x 1 mL per gram of resin), and dried in vacuo. Reaction completion was confirmed by negative Kaiser test where appropriate Coupling of N-terminal Dolavaline-Val-Dil-OH was performed in a similar way ivDde Deprotection and coupling of MDpr(Boc)-OH. After coupling of DolavalineVal-Dil-OH tripeptide, the resin was treated with 2% hydrazine/DMF (1 mL per gram of resin) for 2 hours at RT. Then the resin was washed with DMF (5 x 1 mL per gram of resin), CH2C12 (5 x 1 mL per gram of resin), ethyl ether (5 x 1 mL per gram of resin), and dried in vacuo. A solution of Fmoc-MDpr(Boc)-OH (2 equiv), HATU (2 equiv), and DIEA (4 equiv) in DMF (1 mL per gram of resin) was added to the resin and the mixture was shaken for 3 hours at room temperature (RT). Reaction completion was confirmed by negative Kaiser test. The resin was washed with DMF (5 x 1 mL per gram of resin), CH2C12 (5 x 1 mL per gram of resin), ethyl ether (5 x 1 mL per gram of resin), and dried in vacuo.[0356] Cleavage off the resin and deprotection. Peptide-containing resin was treated with 20% TFA/ CH2C12 (2 mL per gram of resin) for 10 mm at room temperature, and solution was collected in a round bottom flask. The resin was washed with 20% TFA/CH2C12 (2 x 0.5 mL per gram of resin). Pooled solutions were left at RT for 3 hours. After deprotection, completion was confirmed by LC-MS. Volatiles were removed under reduced pressure on Rotavap, and the final product was purified by reverse phase preparative HPLC. All drug-linkers were obtained with>95% purity by reverse phase HPLC at 215nm. Drug-linkers with MA maleimide were prepared in a similar way as described above using ct-maleimidoacetic acid-NHS (Molecular Biosciences, Boulder CO) instead of MDpr(Boc)-OH Drug-linkers with an ethylene diamine (EDA) stretcher were prepared by the procedure similar to the one reported earlier (Bioconjugate Chem. 2008, 19, 1960-1963). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13 mg | In acetonitrile; at 20℃; for 1h; | [0068] To a stirred suspension of maleimidoacetic acid NHS ester (10 mg; 39.7 umol) in anhydrous CH3CN (0.25 mL) was added N-Boc-ethylenediamine (6.3 uL; 39.8 umol). The resulting solution was stirred at room temperature for 1 hr at which time TLC analysis (70% ethyl acetate/30% hexanes; KMn04) showed conversion of the starting material to a new more polar product. The solvent was evaporated and the residue redissolved in ethyl acetate and washed with water, 5% KHS04, water, and brine to furnish the amide as a white solid (13 mg). ]H nmR (CDC13): delta 1.44 (9H, s), 3.26 (2H, m), 3.36 (2H, m), 4.17 (2H, s), 4.88 (1H, br. s), 6.79 (2H, s), 6.83 (1H, br s). TLC: Rf = 0.52 (70% EtOAc/30% hexanes; KMn04). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of Example 2.58.6 (35.1 mg) in N,N-dimethylformamide (4 mL) was added <strong>[55750-61-3]2,5-dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate</strong> (6.93 mg) and N,Ndiisopropylethylamine(0.026 mL). The reaction mixture was stirred at room temperature overnight. Themixture was diluted with N,N-dimethylformamide (2 mL), filtered and purified by reverse-phase HPLC on aGilson system (C18 column), eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid,to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6)6 ppm 12.85 (s, 1H), 8.02 (dd,2H), 7.76 (d, 1H), 7.58 (d, 1H), 7.53-7.37 (m, 3H), 7.32 (td, 2H), 7.24 (s, 1H), 7.16 (dd, 1H), 7.04 (s, 2H),6.99-6.87 (m, 2H), 6.81 (d, 1H), 5.08 (d, 2H), 4.99 (d, 1H), 4.92 (s, 2H), 3.95 (s, 2H), 3.86 (q, 3H), 3.47-3.14(m, 9H), 2.99 (dt, 4H), 2.72 (s, 3H), 2.60 (s, 3H), 2.06 (s, 3H), 1.49 (p, 2H), 1.41-1.27 (m, 4H), 1.29-0.86 (m,10H), 0.80 (d, 7H). MS (ESI) m/e 1413.4 (M-H)-. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of Example 2.58.6 (35.1 mg) in N,N-dimethylformamide (4 mL) was added 2,5- dioxopyrrolidin-l-yl 2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)acetate (6.93 mg) and N,N- diisopropylethylamine (0.026 mL). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with N,N-dimethylformamide (2 mL), filtered and purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, to provide the title compound. NMR (400 MHz, dimethyl sulfoxide-^) delta ppm 12.85 (s, 1H), 8.02 (dd, 2H), 7.76 (d, 1H), 7.58 (d, 1H), 7.53 - 7.37 (m, 3H), 7.32 (td, 2H), 7.24 (s, 1H), 7.16 (dd, 1H), 7.04 (s, 2H), 6.99 - 6.87 (m, 2H), 6.81 (d, 1H), 5.08 (d, 2H), 4.99 (d, 1H), 4.92 (s, 2H), 3.95 (s, 2H), 3.86 (q, 3H), 3.47 - 3.14 (m, 9H), 2.99 (dt, 4H), 2.72 (s, 3H), 2.60 (s, 3H), 2.06 (s, 3H), 1.49 (p, 2H), 1.41 - 1.27 (m, 4H), 1.29 - 0.86 (m, 10H), 0.80 (d, 7H). MS (ESI) m/e 1413.4 (M- H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | Example 2.9.1 (16 mg) was dissolved in N,N-dimethylformamide (0.3 mL), then <strong>[55750-61-3]2,5-dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate</strong> (4 mg) and N-ethyl-N-isopropylpropan-2-amine (11 muL) wereadded. The reaction mixture was stirred for three hours at room temperature, and purification by reversephase chromatography (C18 column), eluting with 10-90% acetonitrile in 0.1% TFA/water, provided the titlecompound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) delta ppm 9.06 (s, 1H), 8.25 (br m, 2H), 8.01 (d, 1H),7.76 (t, 2H), 7.49 (d, 1H), 7.47 (t, 1H), 7.33 (t, 1H), 7.28 (s, 1H), 7.11 (d, 1H), 7.08 (s, 2H), 7.03 (m, 2H),6.56 (d, 1H), 6.17 (m, 1H), 5.00 (s, 2H), 4.86 (br m, 1H), 4.64 (d, 2H), 4.02 (s, 2H), 3.88 (m, 6H), 3.79 (br m,2H), 3.43, 3.35 (m, m, total 14H), 3.22 (s, 3H), 2.80 (m, 2H), 2.57 (m, 2H), 2.09 (s, 3H), 1.37 (br m, 2H),1.28-0.90 (m, 10H), 0.77-0.82 (m, 6H). MS (ESI) m/e 1407.4 (M-1)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.416667h; | [0001210] A cold (0 C) mixture of 2,5-dioxopyrrolidin-l-yl 2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)acetate (566 mg), 1-hydroxybenzotriazole hydrate (229 mg), l-hydroxypyrrolidine-2,5-dione (86 mg) and Example 2.147.2 (440 mg) in N,N-dimethylformamide (3mL) was treated with N,N- diisopropylethylamine (785 mu) for 25 minutes. The reaction was diluted with dimethyl sulfoxide and purified by reverse-phase HPLC on a Gilson system (CI 8 column), eluting with 5-55% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound. MS (ESI) m/e 822.3 (M+H)+. | |
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.416667h; | A cold (0 C) mixture of 2,5-dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)acetate (566 mg), 1-hydroxybenzotriazole hydrate (229 mg), 1-hydroxypyrrolidine-2,5-dione (86 mg) and Example 2.147.2 (440 mg) in N,N-dimethylformamide (3mL) was treated with N,N- diisopropylethylamine (785 muL) for 25 minutes. The reaction was diluted with dimethyl sulfoxide and purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 5-55% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound. MS (ESI) m/e 822.3 (M+H)+. | |
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.416667h; | A cold (0 C.) mixture of <strong>[55750-61-3]2,5-dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate</strong> (566 mg), 1-hydroxybenzotriazole hydrate (229 mg), 1-hydroxypyrrolidine-2,5-dione (86 mg) and Example 2.147.2 (440 mg) in N,N-dimethylformamide (3 mL) was treated with N,N-diisopropylethylamine (785 muL) for 25 minutes. The reaction was diluted with dimethyl sulfoxide and purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 5-55% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound. MS (ESI) m/e 822.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | [000950] A solution of Example 2.49.1 (0.030 g), 2,5-dioxopyrrolidin-l-yl 3-(2,5-dioxo-2,5- dihydro- lH-pyrrol-l-yl)propanoate (6.34 mg) and N,N-diisopropylethylamine (0.012 mL) in N,N- dimethylformamide (0.5 mL) was stirred at room temperature. After 1 hour the reaction was quenched with a 3 : 1 mixture of N,N-dimethylformamide: water (1.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. NMR (500 MHz, dimethyl sulfoxide- g) delta ppm 12.85 (s, 1H), 9.99 (s, 1H), 8.18 (q, 1H), 8.12-8.00 (m, 2H), 7.86-7.75 (m, 2H), 7.65-7.55 (m, 3H), 7.53 (dd, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.36 (q, 2H), 7.33-7.23 (m, 3H), 6.95 (d, 1H), 6.05 (s, 1H), 5.03-4.92 (m, 4H), 4.39 (q, 1H), 4.24-4.14 (m, 1H), 4.02 (s, 2H), 3.88 (t, 2H), 3.81 (d, 2H), 3.39-3.16 (m, 2H), 3.14-2.86 (m, 10H), 2.68- 2.60 (m, 2H), 2.25-2.04 (m, 6H), 2.03- 1.90 (m, 1H), 1.78-1.65 (m, 1H), 1.64- 1.54 (m, 1H), 1.54- 0.90 (m, 20H), 0.89-0.75 (m, 12H). MS (ESI) m/e 1410.1 (M+H)+. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | A solution of Example 2.49.1 (0.039 g), 2,5-dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)acetate (7.81 mg) and N,N-diisopropylethylamine (0.016 mL) in N,N- dimethylformamide (0.5 mL) was stirred at room temperature. After 1 hour, the reaction was quenched with a 3:1 mixture of N,N-dimethylformamide:water (1.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) delta ppm 12.85 (s, 1H), 10.00 (d, 1H), 8.24 (d, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.59 (q, 3H), 7.53 (dd, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.36 (td, 2H), 7.30 (s, 1H), 7.27 (d, 2H), 7.07 (s, 2H), 6.96 (d, 1H), 5.04-4.85 (m, 4H), 4.39 (q, 2H), 4.26 (dd, 2H), 4.13 (s, 2H), 3.86-3.17 (m, 8H), 3.07-2.81 (m, 4H), 2.63 (t, 2H), 2.09 (s, 3H), 2.03-1.79 (m, 1H), 1.75-1.51 (m, 2H), 1.51-1.03 (m, 12H), 1.01-0.76 (m, 16H). MS (ESI) m/e 1394.4 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0001071] Example 2.112.4 (25 mg) and 2,5 -dioxopyrrolidin-l-yl 2-(2,5-dioxo-2,5-dihydro-lH- pyrrol-l-yl)acetate (9.19 mg) in N,N-dimethylformamide (0.3 mL) was treated with N,N- diisopropylethylamine (25.4 mu) for 30 minutes at 0 C. The reaction mixture was purified by reverse-phase HPLC on a Gilson system (CI 8 column), eluting with 35-65% acetonitrile in 4 mM ammonium acetate water mixture, to provide the title compound as an ammonium salt. 1H NMR (400 MHz, dimethyl sulfoxide-^,) delta 12.81 (s, IH), 9.94 (s, IH), 8.01 (dd, 2H), 7.75 (d, 2H), 7.56 (s, 3H), 7.51 - 7.45 (m, IH), 7.45 - 7.37 (m, 2H), 7.36 - 7.28 (m, 2H), 7.24 (t, 3H), 7.17 (s, 2H), 7.05 (s, 3H), 7.04 (s, 2H), 6.92 (s, 3H), 5.93 (s, IH), 5.36 (s, 2H), 5.05 - 4.85 (m, 4H), 4.36 (q, IH), 4.16 (dd, IH), 3.95 (s, 2H), 3.85 (t, 2H), 3.76 (d, 2H), 3.22 (d, 1H), 3.05 - 2.81 (m, 6H), 2.68 - 2.53 (m, 2H), 2.09 (d, 4H), 1.76 - 0.86 (m, 14H), 0.86 - 0.71 (m, 12H). MS (ESI) m/e 1507.5 (M-H)". | ||
Example 2.112.4 (25 mg) and 2,5-dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)acetate (9.19 mg) in N,N-dimethylformamide (0.3 mL) was treated with N,N- diisopropylethylamine (25.4 muL) for 30 minutes at 0 C. The reaction mixture was purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 35-65% acetonitrile in 4 mM ammonium acetate water mixture, to provide the title compound as an ammonium salt. 1H NMR (400 MHz, dimethyl sulfoxide-d6) delta ppm 12.81 (s, 1H), 9.94 (s, 1H), 8.01 (dd, 2H), 7.75 (d, 2H), 7.56 (s, 3H), 7.51- 7.45 (m, 1H), 7.45- 7.37 (m, 2H), 7.36- 7.28 (m, 2H), 7.24 (t, 3H), 7.17 (s, 2H), 7.05 (s, 3H), 7.04 (s, 2H), 6.92 (s, 3H), 5.93 (s, 1H), 5.36 (s, 2H), 5.05- 4.85 (m, 4H), 4.36 (q, 1H), 4.16 (dd, 1H), 3.95 (s, 2H), 3.85 (t, 2H), 3.76 (d, 2H), 3.22 (d, 1H), 3.05- 2.81 (m, 6H), 2.68- 2.53 (m, 2H), 2.09 (d, 4H), 1.76- 0.86 (m, 14H), 0.86- 0.71 (m, 12H). MS (ESI) m/e 1507.5 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.75h; | [0001147] To a mixture of Example 2.127.1 (0.032 g) in N,N-dimethylformamide (0.4 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.025 mL), and the mixture cooled to 0 C. 2,5- Dioxopyrrolidin-l-yl 2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)acetate (8.86 mg) was added in one portion and stirred at 0 C for 45 minutes. The reaction was diluted with a mixture of water (1.5 mL), N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid (0.036 mL) and was purified by preparatory reverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75% acetonitrile/water. The product-containing fractions were lyophilized to give the title compound. NMR (501 MHz, dimethyl sulfoxide-^) delta 12.86 (s, IH), 8.06 (s, IH), 8.02 (dd, IH), 7.77 (d, IH), 7.60 (dd, IH), 7.51 (dd, IH), 7.49 - 7.39 (m, 2H), 7.38 - 7.28 (m, 3H), 7.17 (dd, IH), 7.06 (d, 2H), 6.98 - 6.89 (m, 2H), 6.83 (d, IH), 5.13 - 5.03 (m, 2H), 5.04 - 4.96 (m, IH), 4.94 (s, 2H), 3.97 (s, 2H), 3.90 - 3.77 (m, 6H), 3.50 (s, IH), 3.50 - 3.41 (m, 2H), 3.41 (dt, 3H), 3.28 (dt, 4H), 3.06 - 2.96 (m, 4H), 2.66 (dt, 2H), 2.51 (s, 2H), 2.08 (d, 3H), 1.52 (s, 2H), 1.42 - 1.32 (m, 4H), 1.23 (d, 4H), 1.11 (q, 2H), 1.06 (s, 4H), 0.81 (d, 6H). MS (ESI) m/e 1388.0 (M+H)+. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.75h; | To a mixture of Example 2.127.1 (0.032 g) in N,N-dimethylformamide (0.4 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.025 mL), and the mixture cooled to 0 C. 2,5- Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate (8.86 mg) was added in one portion and stirred at 0 C for 45 minutes. The reaction was diluted with a mixture of water (1.5 mL), N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid (0.036 mL) and was purified by preparatory reverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75% acetonitrile/water. The product-containing fractions were lyophilized to give the title compound. 1H NMR (501 MHz, dimethyl sulfoxide-d6) delta ppm 12.86 (s, 1H), 8.06 (s, 1H), 8.02 (dd, 1H), 7.77 (d, 1H), 7.60 (dd, 1H), 7.51 (dd, 1H), 7.49- 7.39 (m, 2H), 7.38- 7.28 (m, 3H), 7.17 (dd, 1H), 7.06 (d, 2H), 6.98- 6.89 (m, 2H), 6.83 (d, 1H), 5.13- 5.03 (m, 2H), 5.04- 4.96 (m, 1H), 4.94 (s, 2H), 3.97 (s, 2H), 3.90- 3.77 (m, 6H), 3.50 (s, 1H), 3.50- 3.41 (m, 2H), 3.41 (dt, 3H), 3.28 (dt, 4H), 3.06- 2.96 (m, 4H), 2.66 (dt, 2H), 2.51 (s, 2H), 2.08 (d, 3H), 1.52 (s, 2H), 1.42- 1.32 (m, 4H), 1.23 (d, 4H), 1.11 (q, 2H), 1.06 (s, 4H), 0.81 (d, 6H). | |
To a mixture of Example 2.127.1 (0.032 g) in N,N-dimethylformamide (0.4 mL) wasadded N-ethyl-N-isopropylpropan-2-amine (0.025 mL), and the mixture cooled to 0 oc. 2,5-Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate (8.86 mg) was added in oneportion and stirred at 0 oc for 45 minutes. The reaction was diluted with a mixture of water (1.5 mL),35 N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid (0.036 mL) and was purified bypreparatory reverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75% acetonitrile/water. The product-containing fractions were lyophilized to give the title compound. 1HNMR (501 MHz, dimethyl sulfoxide-d6) 8 12.86 (s, 1H), 8.06 (s, 1H), 8.02 (dd, 1H), 7.77 (d, 1H),7.60 (dd, 1H), 7.51 (dd, 1H), 7.49-7.39 (m, 2H), 7.38-7.28 (m, 3H), 7.17 (dd, 1H), 7.06 (d, 2H),6.98-6.89 (m, 2H), 6.83 (d, 1H), 5.13-5.03 (m, 2H), 5.04-4.96 (m, 1H), 4.94 (s, 2H), 3.97 (s,5 2H), 3.90- 3.77 (m, 6H), 3.50 (s, 1H), 3.50-3.41 (m, 2H), 3.41 (dt, 3H), 3.28 (dt, 4H), 3.06-2.96(m, 4H), 2.66 (dt, 2H), 2.51 (s, 2H), 2.08 (d, 3H), 1.52 (s, 2H), 1.42- 1.32 (m, 4H), 1.23 (d, 4H), 1.11(q, 2H), 1.06 (s, 4H), 0.81 (d, 6H). MS (ESI) m/e 1388.0 (M+Ht. |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.75h; | To a mixture of Example 2.127.1 (0.032 g) in N,N-dimethylformamide (0.4 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.025 mL), and the mixture cooled to 0 C. 2,5-Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate (8.86 mg) was added in one portion and stirred at 0 C. for 45 minutes. The reaction was diluted with a mixture of water (1.5 mL), N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid (0.036 mL) and was purified by preparatory reverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75% acetonitrile/water. The product-containing fractions were lyophilized to give the title compound. 1H NMR (501 MHz, dimethyl sulfoxide-d6) delta 12.86 (s, 1H), 8.06 (s, 1H), 8.02 (dd, 1H), 7.77 (d, 1H), 7.60 (dd, 1H), 7.51 (dd, 1H), 7.49-7.39 (m, 2H), 7.38-7.28 (m, 3H), 7.17 (dd, 1H), 7.06 (d, 2H), 6.98-6.89 (m, 2H), 6.83 (d, 1H), 5.13-5.03 (m, 2H), 5.04-4.96 (m, 1H), 4.94 (s, 2H), 3.97 (s, 2H), 3.90-3.77 (m, 6H), 3.50 (s, 1H), 3.50-3.41 (m, 2H), 3.41 (dt, 3H), 3.28 (dt, 4H), 3.06-2.96 (m, 4H), 2.66 (dt, 2H), 2.51 (s, 2H), 2.08 (d, 3H), 1.52 (s, 2H), 1.42-1.32 (m, 4H), 1.23 (d, 4H), 1.11 (q, 2H), 1.06 (s, 4H), 0.81 (d, 6H). MS (ESI) m/e 1388.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.5h; | [0001149] To a mixture of Example 2.133.1 (0.030 g) in N,N-dimethylformamide (0.400 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.023 mL) and the mixture was cooled to 0 C. 2,5- Dioxopyrrolidin-l-yl 2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)acetate (8.34 mg) was added in one portion and he mixture was stirred at 0 C for 30 minutes. The reaction was diluted with a mixture of water (1.5 mL), N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid (0.034 mL) and was purified by preparatory reverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75% acetonitrile/water. The product-containing fractions were lyophilized to give the title compound. NMR (400 MHz, dimethyl sulfoxide- g) delta 13.08 (s, 1H), 9.01 (s, 1H), 8.39 - 8.31 (m, 1H), 8.25 - 8.11 (m, 3H), 8.06 (d, 2H), 7.99 (d, 1H), 7.94 (d, 1H), 7.79 (d, 1H), 7.68 (t, 1H), 7.51 - 7.42 (m, 1H), 7.46 (s, 1H), 7.35 (t, 1H), 7.22 - 7.13 (m, 1H), 7.06 (d, 2H), 6.93 (d, 1H), 6.83 (d, 1H), 5.15 - 5.00 (m, 2H), 4.99 (d, 1H), 3.97 (s, 2H), 3.86 (d, 3H), 3.42 (d, 4H), 3.29 (d, 5H), 3.03 (p, 2H), 2.72 - 2.62 (m, 2H), 2.51 (d, 3H), 2.21 (s, 3H), 1.51 (q, 2H), 1.37 (q, 4H), 1.24 (d, 4H), 1.10 (s, 5H), 0.83 (d, 6H), 0.61 (s, 2H). MS (ESI) m/e 1383.0 (M+H)+. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.5h; | To a mixture of Example 2.133.1 (0.030 g) in N,N-dimethylformamide (0.400 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.023 mL) and the mixture was cooled to 0 C. 2,5- Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate (8.34 mg) was added in one portion and he mixture was stirred at 0 C for 30 minutes. The reaction was diluted with a mixture of water (1.5 mL), N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid (0.034 mL) and was purified by preparatory reverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75% acetonitrile/water. The product-containing fractions were lyophilized to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) delta ppm 13.08 (s, 1H), 9.01 (s, 1H), 8.39- 8.31 (m, 1H), 8.25 - 8.11 (m, 3H), 8.06 (d, 2H), 7.99 (d, 1H), 7.94 (d, 1H), 7.79 (d, 1H), 7.68 (t, 1H), 7.51- 7.42 (m, 1H), 7.46 (s, 1H), 7.35 (t, 1H), 7.22- 7.13 (m, 1H), 7.06 (d, 2H), 6.93 (d, 1H), 6.83 (d, 1H), 5.15- 5.00 (m, 2H), 4.99 (d, 1H), 3.97 (s, 2H), 3.86 (d, 3H), 3.42 (d, 4H), 3.29 (d, 5H), 3.03 (p, 2H), 2.72- 2.62 (m, 2H), 2.51 (d, 3H), 2.21 (s, 3H), 1.51 (q, 2H), 1.37 (q, 4H), 1.24 (d, 4H), 1.10 (s, 5H), 0.83 (d, 6H), 0.61 (s, 2H). MS (ESI) m/e 1383.0 (M+H)+. | |
To a mixture of Example 2.127.1 (0.032 g) in N,N-dimethylformamide (0.4 mL) wasadded N-ethyl-N-isopropylpropan-2-amine (0.025 mL), and the mixture cooled to 0 oc. 2,5-Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate (8.86 mg) was added in oneportion and stirred at 0 oc for 45 minutes. The reaction was diluted with a mixture of water (1.5 mL),35 N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid (0.036 mL) and was purified bypreparatory reverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75% acetonitrile/water. The product-containing fractions were lyophilized to give the title compound. 1HNMR (501 MHz, dimethyl sulfoxide-d6) 8 12.86 (s, 1H), 8.06 (s, 1H), 8.02 (dd, 1H), 7.77 (d, 1H),7.60 (dd, 1H), 7.51 (dd, 1H), 7.49-7.39 (m, 2H), 7.38-7.28 (m, 3H), 7.17 (dd, 1H), 7.06 (d, 2H),6.98-6.89 (m, 2H), 6.83 (d, 1H), 5.13-5.03 (m, 2H), 5.04-4.96 (m, 1H), 4.94 (s, 2H), 3.97 (s,5 2H), 3.90- 3.77 (m, 6H), 3.50 (s, 1H), 3.50-3.41 (m, 2H), 3.41 (dt, 3H), 3.28 (dt, 4H), 3.06-2.96(m, 4H), 2.66 (dt, 2H), 2.51 (s, 2H), 2.08 (d, 3H), 1.52 (s, 2H), 1.42- 1.32 (m, 4H), 1.23 (d, 4H), 1.11(q, 2H), 1.06 (s, 4H), 0.81 (d, 6H). MS (ESI) m/e 1388.0 (M+Ht. |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.5h; | To a mixture of Example 2.133.1 (0.030 g) in N,N-dimethylformamide (0.400 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.023 mL) and the mixture was cooled to 0 C. 2,5-Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate (8.34 mg) was added in one portion and he mixture was stirred at 0 C. for 30 minutes. The reaction was diluted with a mixture of water (1.5 mL), N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid (0.034 mL) and was purified by preparatory reverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75% acetonitrile/water. The product-containing fractions were lyophilized to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) delta 13.08 (s, 1H), 9.01 (s, 1H), 8.39-8.31 (m, 1H), 8.25-8.11 (m, 3H), 8.06 (d, 2H), 7.99 (d, 1H), 7.94 (d, 1H), 7.79 (d, 1H), 7.68 (t, 1H), 7.51-7.42 (m, 1H), 7.46 (s, 1H), 7.35 (t, 1H), 7.22-7.13 (m, 1H), 7.06 (d, 2H), 6.93 (d, 1H), 6.83 (d, 1H), 5.15-5.00 (m, 2H), 4.99 (d, 1H), 3.97 (s, 2H), 3.86 (d, 3H), 3.42 (d, 4H), 3.29 (d, 5H), 3.03 (p, 2H), 2.72-2.62 (m, 2H), 2.51 (d, 3H), 2.21 (s, 3H), 1.51 (q, 2H), 1.37 (q, 4H), 1.24 (d, 4H), 1.10 (s, 5H), 0.83 (d, 6H), 0.61 (s, 2H). MS (ESI) m/e 1383.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A round bottom flask was charged with 1-(4-(4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)piperazin-1 -yl)-3-(2-(2-aminoethoxy)ethoxy)propan-1 - one (C-20) (1 .0 equiv.), DIEA (10.0 equiv.) and DMF (0.004 M) and the mixture was stirred at room temperature for 15 minutes. A separate flask was then charged with 2,5-dioxopyrrolidin-1- yl 2-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1 -yl)acetate (1 .5 equiv.), DIEA (10.0 equiv.) and DMF(0.006 M). This mixture was also stirredfor 15 minutes at room temperature and then the two solutions were mixed and the reaction mixture stirred at room temperature for 1 hour. The crude reaction mixture was was purified by RP-HPLC (0.035% TFA in ACN:0.05% TFA in H20, C18 column) to afford N-(2-(2-(3-(4-(4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5- yl)methyl)-3-methoxybenzyl)piperazin-1 -yl)-3-oxopropoxy)ethoxy)ethyl)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamide (C-21) as a solid as the TFA salt: 1H NMR (CD3CN): 3 7.30 (d,1H), 7.05 (5, 1H), 6.98 (5, 1H), 6.86 (d, 1H), 6.82 (5, 2H), 6.74 (5, 1H), 6.68 (d, 1H), 6.21 (d, 1H), 6.08 (t, 1H), 5.38 (5, 2H), 4.08 (5, 2H), 3.89 (5, 3H), 3.70 (t, 2H), 3.41 (m, 14H), 3.29 (m, 2H), 2.55, (t, 2H), 2.38 (m, 4H), 1.41 (m, 2H), 1.26 (m, 2H), 1.13 (m, 2H), 0.85 (t, 3H). LCMS [M+H] = 734.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example 2 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-((3-(1-(2-(9-hydroxy-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl)piperidin-4-yl)benzo[d]isoxazol-6-yl)oxy)ethyl)acetamide To a solution of 3-(2-(4-(6-(2-aminoethoxy)benzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in Example 1, (4.0 mg, 8.5 mumoles) in 215 muL of DMF and 4.3 muL of tributylamine was added 214 muL of a DMF solution of N-(alpha-maleimidoacetoxy)succinimide ester (AMAS, 10 mg/mL, 2.1 mg, 8.5 mumoles). The resulting solution was allowed to stir for 60 minutes at 20 C., then used as such in conjugation reaction with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1.5h; | Example 4 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-((3-(1-(2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl)piperidin-4-yl)benzo[d]isoxazol-6-yl)oxy)ethyl)acetamide To a solution of 3-(2-(4-(6-(2-aminoethoxy)benzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in Example 3, (3.4 mg, 7.58 mumoles) in 185 muL of DMF and 3.7 muL of tributylamine was added 190 muL of a DMF solution of N-(alpha-maleimidoacetoxy)succinimide ester (AMAS, 10 mg/mL, 1.9 mg, 7.58 mumoles). The resulting solution was allowed to stir for 90 minutes at 20 C., then used as such in conjugation reaction with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
116 g | With triethylamine; In dichloromethane; at 20℃; for 2h; | To a 500 ml three-necked flask, N-maleimidyl acetic acid (94 g, 0.6 mol)And dichloromethane 300ml,Oxalyl chloride (90 g, 0.72 mol) was then added,The reaction was warmed to reflux, a large amount of gas was released.After 2h the reaction became clear,Concentrate to remove methylene chloride and excess oxalyl chloride,Addition of 200 ml of methylene chloride to remove the residual acid in one pass afforded crude N-maleimidoacetyl chloride.The crude product was dissolved in 200 ml of dichloromethane,Was added dropwise to N-hydroxysuccinimide (69 g, 0.6 mol)Triethylamine (80.8 g, 0.8 mol)Dissolved in 300 ml of dichloromethane,Ice water cooling control temperature does not exceed 20 , drip finished room temperature 2h.The reaction solution was washed with 200 ml of water to remove triethylamine hydrochloride,1N hydrochloric acid 100ml washing to remove excess triethylamine,200ml saturated salt water, washed and dried,Concentrated to dry off like white solid 137g,After recrystallization from a mixed solvent of ethyl acetate and petroleum ether, 116 g of a white solid was obtained,HPLC purity 98.7%, 76.7% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | Example 2.9.1 (16 mg) was dissolved in N,N-dimethylformamide (0.3 mL), then 2,5- dioxopyrrolidin-l-yl 2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)acetate (4 mg) and N-ethyl-N- isopropylpropan-2-amine (11 mu) were added. The reaction mixture was stirred for three hours at room temperature, and purification by reverse phase chromatography (CI 8 column), eluting with 10- 90% acetonitrile in 0.1%) TF A/water, provided the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) delta ppm 9.06 (s, 1H), 8.25 (br m, 2H), 8.01 (d, 1H), 7.76 (t, 2H), 7.49 (d, 1H), 7.47 (t, 1H), 7.33 (t, 1H), 7.28 (s, 1H), 7.11 (d, 1H), 7.08 (s, 2H), 7.03 (m, 2H), 6.56 (d, 1H), 6.17 (m,lH), 5.00 (s, 2H), 4.86 (br m, 1 H), 4.64 (d, 2H), 4.02 (s, 2H), 3.88 (m, 6H), 3.79 (br m, 2H), 3.43, 3.35 (m, m, total 14H), 3.22 (s, 3H), 2.80 (m, 2H), 2.57 (m, 2H), 2.09 (s, 3H), 1.37 (br m, 2H), 1.28-0.90 (m, 10H), 0.77-0.82 (m, 6H). MS (ESI) m/e 1407.4 (M-l)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of Example 2.5S.6 (35.I mg) in N,N-dimethylformamide (4 mL) was added 2,5-dioxopyrrolidin-I-yl 2-(2,5-dioxo-2,5-dihydro-IH-pyrrol-I-yl)acetate (6.93 mg) and N,Ndiisopropylethylamine(0.026 mL). The reaction mixture was stirred at room temperature overnight.20 The mixture was diluted with N,N-dimethylformamide (2 mL), filtered and purified by reverse-phaseHPLC on a Gilson system (CIS column), eluting with 20-SO% acetonitrile in water containing O.I%trifluoroacetic acid, to provide the title compound. 1H NMR ( 400 MHz, dimethyl sulfoxide-d6) 8 ppmI2.S5 (s, IH), S.02 (dd, 2H), 7.76 (d, IH), 7.5S (d, IH), 7.53- 7.37 (m, 3H), 7.32 (td, 2H), 7.24 (s,IH), 7.I6 (dd, IH), 7.04 (s, 2H), 6.99- 6.S7 (m, 2H), 6.SI (d, IH), 5.0S (d, 2H), 4.99 (d, IH), 4.92 (s,25 2H), 3.95 (s, 2H), 3.S6 (q, 3H), 3.47- 3.I4 (m, 9H), 2.99 (dt, 4H), 2.72 (s, 3H), 2.60 (s, 3H), 2.06 (s,3H), 1.49 (p, 2H), 1.4I- 1.27 (m, 4H), 1.29- O.S6 (m, IOH), O.SO (d, 7H). MS (ESI) m/e I413.4 (MH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | A solution of Example 2.49.1 (0.039 g), 2,5-dioxopyrrolidin-1-yl2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate (7.81 mg) and N,N-diisopropylethylamine (0.016 mL) in N,Ndimethylformamide(0.5 mL) was stirred at room temperature. After 1 hour, the reaction wasquenched with a 3:1 mixture of N,N-dimethylformamide:water (1.5 mL). The mixture was purified15 by reverse phase HPLC using a Gilson system, eluting with 10-85% acetonitrile in water containing0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide thetitle compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 8 ppm 12.85 (s, 1H), 10.00 (d, 1H), 8.24(d, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.59 (q, 3H), 7.53 (dd, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.36 (td,2H), 7.30 (s, 1H), 7.27 (d, 2H), 7.07 (s, 2H), 6.96 (d, 1H), 5.04-4.85 (m, 4H), 4.39 (q, 2H), 4.26 (dd,20 2H), 4.13 (s, 2H), 3.86-3.17 (m, 8H), 3.07-2.81 (m, 4H), 2.63 (t, 2H), 2.09 (s, 3H), 2.03-1.79 (m, 1H),1.75-1.51 (m, 2H), 1.51-1.03 (m, 12H), 1.01-0.76 (m, 16H). MS (ESI) m/e 1394.4 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2.112.4 (25 mg) and 2,5-dioxopyrrolidin-1-yl2-(2,5-dioxo-2,5-dihydro-1H-5 pyrrol-1-yl)acetate (9.19 mg) in N,N-dimethylformamide (0.3 mL) was treated with N,Ndiisopropylethylamine(25.4 f1L) for 30 minutes at 0 C. The reaction mixture was purified byreverse-phase HPLC on a Gilson system (CIS column), eluting with 35-65% acetonitrile in 4 mMammonium acetate water mixture, to provide the title compound as an ammonium salt. 1H NMR ( 400MHz, dimethyl sulfoxide-d6) 8 12.81 (s, IH), 9.94 (s, IH), 8.01 (dd, 2H), 7.75 (d, 2H), 7.56 (s, 3H),10 7.51 -7.45 (m, IH), 7.45-7.37 (m, 2H), 7.36-7.28 (m, 2H), 7.24 (t, 3H), 7.17 (s, 2H), 7.05 (s, 3H),7.04 (s, 2H), 6.92 (s, 3H), 5.93 (s, IH), 5.36 (s, 2H), 5.05-4.85 (m, 4H), 4.36 (q, IH), 4.16 (dd, IH),3.95 (s, 2H), 3.85 (t, 2H), 3.76 (d, 2H), 3.22 (d, IH), 3.05-2.81 (m, 6H), 2.68-2.53 (m, 2H), 2.09(d, 4H), 1.76-0.86 (m, 14H), 0.86-0.71 (m, 12H). MS (ESI) m/e 1507.5 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-pyrrolidine-2,5-dione; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.416667h; | A cold (0 C) mixture of 2,5-dioxopyrrolidin-I-yl2-(2,5-dioxo-2,5-dihydro-IH-pyrrol-Iyl)acetate (566 mg), I-hydroxybenzotriazole hydrate (229 mg), I-hydroxypyrrolidine-2,5-dione (S6mg) and Example 2.I47.2 (440 mg) in N,N-dimethylformamide (3mL) was treated with N,N-35 diisopropylethylamine (7S5 f1L) for 25 minutes. The reaction was diluted with dimethyl sulfoxideand purified by reverse-phase HPLC on a Gilson system (CIS column), eluting with 5-55% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound. MS (ESI) m/e822.3 (M+Ht. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of 2-(2-(2-(aminomethyl)-4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)ethoxy)ethanol, prepared as described in Example 1, (7.8 mg, 19.0 mumoles) in 410 muL of DMF and 8.9 muL of tributylamine was added 480 muL of a DMF solution of N-(alpha-maleimidoacetoxy) succinimide ester (AMAS, 10 mg/mL, 4.8 mg, 19.0 mumoles). The resulting solution was allowed to stir for 60 minutes at 20 C., then used as such in conjugation reaction with thiol-activated protein. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; | 107 mg (0.335 mmol) of tert-butyl 3-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy ]ethoxy ]propanoate and 93mg (0.369 mmol) of <strong>[55750-61-3](2,5-dioxopyrrolidin-1-yl) 2-(2,5-dioxopyrrol-1-yl)acetate</strong> were dissolved in 5 ml ofdimethylformamide, and 0.074 ml (0.671 mmol) of N-methylmorpholine were added. The reactionmixture was stirred at RT overnight. 0.048 ml (0.838 mmol) of acetic acid were added and the reaction20 mixture was purified directly by preparative RP-HPLC (column: Reprosil 125x30; 1011, flow rate: 50ml/min, MeCN/water/0.1% TF A). The solvents were evaporated under reduced pressure and the residuewas dried under high vacuum. This gave 133 mg (86%, purity 100%) of tert-butyl 3-[2-[2-[2-[2-[[2-(2,5-dioxopyrrol-1-yl)acetyl]amino ]ethoxy ]ethoxy ]ethoxy ]ethoxy ]propanoate.25 LC-MS (Method 1): Rt = 0.82 min; MS (ESipos): m/z = 459 (M+Ht. |
86% | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; | 107 mg (0.335 mmol) of tert-butyl 3-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]propanoate and 93 mg (0.369 mmol) of <strong>[55750-61-3](2,5-dioxopyrrolidin-1-yl) 2-(2,5-dioxopyrrol-1-yl)acetate</strong> were dissolved in 5 ml of dimethylformamide, and 0.074 ml (0.671 mmol) of N-methylmorpholine was added. The reaction mixture was stirred at RT overnight. 0.048 ml (0.838 mmol) of acetic acid was added and the reaction mixture was purified directly by preparative RP-HPLC (column: Reprosil 125*30; 10mu, flow rate: 50 ml/min, MeCN/water/0.1% TFA). The solvents were evaporated under reduced pressure and the residue was dried under high vacuum. This gave 133 mg (86%, 100% purity) of tert-butyl 3-[2-[2-[2-[2-[[2-(2,5-dioxopyrrol-1-yl)acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propanoate. LC-MS (Method 1): Rt=0.82 min; MS (ESIpos): m/z=459 (M+H)+. |
86%, purity 100% | With 4-methyl-morpholine; acetic acid; trifluoroacetic acid; | 107 mg (0.335 mmol) of tert-butyl 3-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]propanoate and 93 mg (0.369 mmol) of <strong>[55750-61-3](2,5-dioxopyrrolidin-1-yl) 2-(2,5-dioxopyrrol-1-yl)acetate</strong> were dissolved in 5 ml of dimethylformamide, and 0.074 ml (0.671 mmol) of N-methylmorpholine were added. The reaction mixture was stirred at RT overnight. 0.048 ml (0.838 mmol) of acetic acid were added and the reaction mixture was purified directly by preparative RP-HPLC (column: Reprosil 125*30; 10mu, flow rate: 50 ml/min, MeCN/water/0.1% TFA). The solvents were evaporated under reduced pressure and the residue was dried under high vacuum. This gave 133 mg (86%, purity 100%) of tert-butyl 3-[2-[2-[2-[2-[[2-(2,5-dioxopyrrol-1-yl)acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propanoate. LC-MS (Method 1): Rt=0.82 min; MS (ESIpos): m/z=459 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | a solution of 2-((6aR,7S,8aS,8bS,1 OR,11aR,12aS,12bS)-10-(4-(3-((S)-2-((S)-2-((tertbutoxycarbonyl)amino)propanamido)propanamido)benzyl)phenyl)-7-hydroxy-6a,8a-dime thyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethy12-(dimethylamino)acetate(82 mg,0.074 mmol)in DCM(4 mL)and TFa(1 mL)was stirred atroom temperature for 20 minutes,and then concentrated in vacuo. To a solution of this compound inanhydrous N,N-dimethylformamide(1 mL)was added Hunig's base(0.20 mL,1.15 mmol)and <strong>[55750-61-3]2,5-dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate</strong>(27 .8mg,0.11 mmol). Theresulting mixture was stirred at room temperature for 15 minutes,and TFa(0.106 mL,1.376 mmol)wasadded. The crude product was purified by Cl8 HPLC,eluting with a solvent gradient of 5-95% MeCN inO.lM aqueous TFa. Fractions containing the pure product were concentrated bylyophilization to affordthe title compound as a co10Rless solid(46 mg,0.0439 mmol,59% yield). LCMS(Method r,Table 7)major acetal isomer R1=0.82 min,MS m/z = 934 [M+H+]; minor acetal isomer R1= =0.81 min,MS m/z =934 [M+H+],1H NMR(501 MHz,DMSO-d6)8 10.12(s,2H),9.75(s,1H),8.40(d,J = 7.3 Hz,1H),8.11(d,J = 7.1 Hz,1H),7.45- 7.42(m,1H),7.38(dd,J = 8.2,2.0 Hz,2H),7.31(d,J = 10.1 Hz,1H),7.22(d,J = 8.2 Hz,2H),7.17(t,J = 7.8 Hz,1H),7.06(s,1H),6.89(d,J = 7.7 Hz,1H),6.50(s,1H),6.15(dd,J =10.1,1.9 Hz,1H),5.93- 5.90(m,1H),5.52(s,1H),5.30(d,J = 17.7 Hz,1H),5.00(d,J = 17.7 Hz,1H),4.86(t,J = 5.0 Hz,2H),4.36- 4.25(m,4H),4.12- 4.02(m,2H),3.87(s,1H),2.82(s,3H),2.56- 2.51(m,1H),2.50(s,OH),2.50(d,J = 1.8 Hz,OH),2.33- 2.26(m,2H),2.15- 2.06(m,2H),2.04- 1.97(m,2H),1.84- 1.80(m,1H),1.77- 1.60(m,4H),1.37(s,3H),1.26(d,J = 7.1 Hz,3H),1.19(d,J = 7.1 Hz,3H),1.10- 0.98(m,3H),0.89(s,3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | A solution of Example 2.49.1 (0.039 g), <strong>[55750-61-3]2,5-dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate</strong> (7.81 mg) and N,N-diisopropylethylamine (0.016 mL) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature. After 1 hour, the reaction was quenched with a 3:1 mixture of N,N-dimethylformamide:water (1.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) delta ppm 12.85 (s, 1H), 10.00 (d, 1H), 8.24 (d, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.59 (q, 3H), 7.53 (dd, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.36 (td, 2H), 7.30 (s, 1H), 7.27 (d, 2H), 7.07 (s, 2H), 6.96 (d, 1H), 5.04-4.85 (m, 4H), 4.39 (q, 2H), 4.26 (dd, 2H), 4.13 (s, 2H), 3.86-3.17 (m, 8H), 3.07-2.81 (m, 4H), 2.63 (t, 2H), 2.09 (s, 3H), 2.03-1.79 (m, 1H), 1.75-1.51 (m, 2H), 1.51-1.03 (m, 12H), 1.01-0.76 (m, 16H). MS (ESI) m/e 1394.4 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2.112.4 (25 mg) and <strong>[55750-61-3]2,5-dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate</strong> (9.19 mg) in N,N-dimethylformamide (0.3 mL) was treated with N,N-diisopropylethylamine (25.4 muL) for 30 minutes at 0 C. The reaction mixture was purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 35-65% acetonitrile in 4 mM ammonium acetate water mixture, to provide the title compound as an ammonium salt. 1H NMR (400 MHz, dimethyl sulfoxide-d6) delta 12.81 (s, 1H), 9.94 (s, 1H), 8.01 (dd, 2H), 7.75 (d, 2H), 7.56 (s, 3H), 7.51-7.45 (m, 1H), 7.45-7.37 (m, 2H), 7.36-7.28 (m, 2H), 7.24 (t, 3H), 7.17 (s, 2H), 7.05 (s, 3H), 7.04 (s, 2H), 6.92 (s, 3H), 5.93 (s, 1H), 5.36 (s, 2H), 5.05-4.85 (m, 4H), 4.36 (q, 1H), 4.16 (dd, 1H), 3.95 (s, 2H), 3.85 (t, 2H), 3.76 (d, 2H), 3.22 (d, 1H), 3.05-2.81 (m, 6H), 2.68-2.53 (m, 2H), 2.09 (d, 4H), 1.76-0.86 (m, 14H), 0.86-0.71 (m, 12H). MS (ESI) m/e 1507.5 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N-[(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]-L-alanyl-L-alanyl-L-asparagine The title compound was prepared by conventional methods of peptide chemistry by HATU coupling of commercially available N-[(benzyloxy)carbonyl]-L-alanyl-L-alanine with tert-butyl L-asparaginate, in the presence of N,N-diisopropylethylamine, subsequent deprotection of the Z protecting group by hydrogenation in DCM/methanol over 10% palladium on activated carbon, followed by acylation with <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> in DMF in the presence of N,N-diisopropylethylamine and finally deprotection of the carboxyl group by means of trifluoroacetic acid. LC-MS (Method 1): Rt=0.35 min; MS (ESIpos): m/z=412 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N-[(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]-L-valyl-N-{(1S)-3-[{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}(glycoloyl)amino]-1-carboxypropyl}-L-alaninamide 41 mg (0.05 mmol) of Intermediate C76 dissolved in 12 ml of methanol were hydrogenated over 10 mg of 10% palladium on activated carbon at RT for 1 h under hydrogen standard pressure. The catalyst was then filtered off and the solvent was removed under reduced pressure. This gave 32 mg (92% of theory) of the deprotected intermediate. 15 mg (0.022 mmol) of this intermediate were dissolved in 4 ml of DMF, and 10 mg (0.039 mmol) of <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> and 7 mul of N,N-diisopropylethylamine were added. After 2 h of stirring at RT, the reaction was concentrated and the residue was purified by HPLC. This gave 10 mg (56% of theory) of the title compound. LC-MS (Method 1): Rt=1.08 min; MS (ESIpos): m/z=821 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; acetic acid; trifluoroacetic acid; | N-[3-({2-[(3-Aminopropyl) {(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}amino]-2-oxoethyl}sulphanyl)propanoyl]-3-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]amino}-D-alanine/trifluoroacetic Acid (1:1) 10.0 mg (9.98 mumol) of trifluoroacetic acid/2-(trimethylsilyl)ethyl 3-amino-N-(11-{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}-2,2-dimethyl-6,12,17-trioxo-5-oxa-14-thia-7,11-diaza-2-silaheptadecan-17-yl)-D-alaninate (1:1) (Intermediate C80) and 2.77 mg (11.0 mumol) of <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> were dissolved in 1 ml of dimethylformamide, and 3.3 mul (30 mumol) of N-methylmorpholine were added. The reaction mixture was stirred at RT overnight. 2.0 mul (35 mumol) of acetic acid were added, and the reaction mixture was purified directly by preparative RP-HPLC (column: Reprosil 125*30; 10mu, flow rate: 50 ml/min, MeCN/water/0.1% TFA). The solvents were evaporated under reduced pressure and the residue was dried under high vacuum. This gave 5.50 mg (54% of theory) of the compound 2-(trimethylsilyl)ethyl N-(11-{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}-2,2-dimethyl-6,12,17-trioxo-5-oxa-14-thia-7,11-diaza-2-silaheptadecan-17-yl)-3-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]amino}-D-alaninate. LC-MS (Method 1): Rt=1.51 min; MS (ESIpos): m/z=1024 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; | N-[3-({2-[(3-Aminopropyl){(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}amino]-2-oxoethyl}sulphanyl) propanoyl]-3-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]amino}-D-alanine/trifluoroacetic acid (1:1) 10.0 mg (9.98 mumol) of trifluoroacetic acid/-2-(trimethylsilyl)ethyl 3-amino-N-(11-{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}-2,2-dimethyl-6,12,17-trioxo-5-oxa-14-thia-7,11-diaza-2-silaheptadecan-17-yl)-D-alaninate (1:1) (Intermediate C80) and 2.77 mg (11.0 mumol) of <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> were dissolved in 1 ml of dimethylformamide, and 3.3 mul (30 mumol) of N-methylmorpholine were added. The reaction mixture was stirred at RT overnight. 2.0 mul (35 mumol) of acetic acid were added to the reaction mixture, which was purified directly by preparative RP-HPLC (column: Reprosil 125*30; 10mu, flow rate: 50 ml/min, MeCN/water/0.1% TFA). The solvents were evaporated under reduced pressure and the residue was dried under high vacuum. This gave 5.50 mg (54% of theory) of the compound 2-(trimethylsilyl)ethyl N-(11-{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}-2,2-dimethyl-6,12,17-trioxo-5-oxa-14-thia-7,11-diaza-2-silaheptadecan-17-yl)-3-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]amino}-D-alaninate. LC-MS (Method 1): Rt=1.51 min; MS (ESIpos): m/z=1024 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Trifluoroacetic acid di-tert-butyl-(2R)-2-[(4S,7R,10S)-10-(2-amino-2-oxoethyl)-16-{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4,7-dimethyl-2,5,8,11,17,22-hexaoxo-19-thia-3,6,9,12,16-pentaazadocosan-22-yl]amino}succinate salt Di-tert-butyl (2R)-2-[(2S,5R,8S)-2-amino-8-(2-amino-2-oxoethyl)-14-{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}-5-methyl-3,6,9,15,20-pentaoxo-17-thia-4,7,10,14-tetraazaicosan-20-yl]amino}succinate (12.0 mg, 11.5 mumol, Intermediate C126) and <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> (3.20 mg, 12.7 mumol) were dissolved in DMF (1.0 ml), and N,N-diisopropylethylamine (4.0 mul, 23 mumol) was added. The mixture was stirred at room temperature for 1 h. This was followed by quenching with water+0.1% TFA, and direct purification of the mixture by means of preparative RP-HPLC. The solvents were evaporated under reduced pressure and the residue was dried under high vacuum. LC-MS (Method 1): Rt=1.25 min; MS (ESIpos): m/z=1178 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N-[(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]-L-alanyl-D-alanyl-N1-{(2S)-4-[{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}(glycoloyl)amino]-1-[(3-[(1S)-1,3-dicarboxypropyl]amino}-3-oxopropyl)amino]-1-oxobutan-2-yl}-L-aspartamide The title compound was prepared proceeding from compound C110, first by coupling to Intermediate L108 in the presence of HATU and N,N-diisopropylethylamine. In the next step, all protecting groups were removed by hydrogenation over 10% palladium on activated carbon in methanol under standard hydrogen pressure at RT for 1 hour and the deprotected intermediate was then converted to the title compound by reaction with <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> in the presence of N,N-diisopropylethylamine. LC-MS (Method 1): Rt=0.94 min; MS (ESIpos): m/z=1107 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N-(Pyridin-4-ylacetyl)-L-alanyl-D-alanyl-N1-[(2S)-4-[{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}(glycoloyl)amino]-1-[2-({N-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]-D-alpha-glutamyl}amino)ethyl]amino}-1-oxobutan-2-yl]-L-aspartamide The synthesis of the title compound commenced with the coupling of Intermediate C102 to Intermediate L131 in the presence of HATU and N,N-diisopropylethylamine. This was followed by hydrogenolytic detachment of the Z group with hydrogen under standard pressure over 10% palladium/activated carbon in ethanol. This was followed by coupling to Intermediate L110 in DMF in the presence of HATU and N,N-diisopropylethylamine. Then the Boc protecting group and the tert-butyl ester were detached by stirring with 6 equivalents of zinc chloride in trifluoroethanol at 50 C. for 6 h. In the last step, the intermediate obtained was coupled to <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> in DMF in the presence of N,N-diisopropylethylamine and, after purification by preparative HPLC, the title compound was obtained. LC-MS (Method 12): Rt=Rt=1.49 min; MS (ESIpos): m/z=1197 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | N-[(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]-L-valyl-N-{(1S)-3-[{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}(glycoloyl)amino]-1-carboxypropyl}-L-alaninamide 41 mg (0.05 mmol) of Intermediate C76 dissolved in 12 ml of methanol were hydrogenated over 10 mg of 10% palladium on activated carbon at RT for 1 h under hydrogen standard pressure. The catalyst was then filtered off and the solvent was removed under reduced pressure. This gave 32 mg (92% of theory) of the deprotected intermediate. 15 mg (0.022 mmol) of this intermediate were dissolved in 4 ml of DMF, and 10 mg (0.039 mmol) of <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> and 7 mul of N,N-diisopropylethylamine were added. After stirring at RT for 2 h, the reaction mixture was concentrated and the residue was purified by HPLC. This gave 10 mg (56% of theory) of the title compound. LC-MS (Method 1): Rt=1.08 min; MS (ESIpos): m/z=821 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The title compound was prepared by coupling Intermediate C102 to tert-butyl (2-aminoethyl)carbamate in the presence of HATU and N,N-diisopropylethylamine, subsequent detachment of the Z protecting group by hydrogenation over 10% palladium on activated carbon in DCM-methanol 1:1 under standard hydrogen pressure at RT for 1 hour, followed by coupling to 4-nitrophenyl N2-[(benzyloxy)carbonyl]-L-asparaginate in DMF and subsequent detachment of the Z protecting group by hydrogenation over 10% palladium on activated carbon in ethanol under standard hydrogen pressure at RT for 1 hour. This intermediate was subsequently coupled to N-[(9H-fluoren-9-ylmethoxy)carbonyl]-1-[2-(trimethylsilyl)ethoxy]carbonyl}-D-histidine, which had been prepared beforehand by reaction of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-D-histidine with 1-([2-(trimethylsilyl)ethoxy]carbonyl}-oxy)pyrrolidine-2,5-dione in the presence of N,N-diisopropylethylamine in DMF, in the presence of HATU and N,N-diisopropylethylamine in DMF. Then the Fmoc protecting group was detached with piperidine in DMF. The deprotected compound was coupled in the presence of HATU and N,N-diisopropylethylamine to N-(pyridin-4-ylacetyl)-L-alanine hydrochloride (1:1) which had been prepared beforehand by reaction of pyridin-4-ylacetic acid hydrochloride (1:1) with tert-butyl L-alaninate hydrochloride (1:1) by means of HATU, and subsequent tert-butyl ester hydrolysis with TFA in DCM. The Boc group was detached from the intermediate obtained by stirring at 50 C. in trifluoroethanol with 6 equiv. of zinc chloride for one hour. In the last step, the title compound was obtained by reaction with <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> in DMF in the presence of N,N-diisopropylethylamine. LC-MS (Method 1): Rt=0.75 min; MS (ESIpos): m/z=1134 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | S-[2-({(1R)-1-[1-Benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}amino)-2-oxoethyl]-N-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]-L-cysteine (Isomer 1) 18.5 mg (0.14 mmol) of N,N-diisopropylethylamine were added to a mixture of 50.0 mg (0.07 mmol) of S-[2-({(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}[-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}amino)-2-oxoethyl]-L-cysteine (Intermediate C90) and 18.0 mg (0.07 mmol) of -<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong> in 3.3 ml of DMF, and the reaction mixture was stirred at RT for 30 minutes. Ethyl acetate was added to the reaction mixture and the organic phase was washed repeatedly with saturated NH4Cl solution and once with saturated NaCl solution. The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure. The residue was used without further purification. This gave 57 mg (81% of theory, 85% pure) of the title compound. LC-MS (Method 1): Rt=0.96 min; MS (ESIpos): m/z=836 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N-[(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]-L-alanyl-D-alanyl-L-asparagine The title compound was prepared by conventional methods of peptide chemistry by HATU coupling of N-[(benzyloxy)carbonyl]-L-alanyl-D-alanine to tert-butyl L-asparaginate, in the presence of N,N-diisopropylethylamine, subsequent deprotection of the Z protecting group by hydrogenation in methanol over 10% palladium on activated carbon, followed by acylation with <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> in DMF in the presence of N,N-diisopropylethylamine and finally deprotection of the carboxyl group by means of trifluoroacetic acid. LC-MS (Method 1): Rt=0.18 min; MS (ESIpos): m/z=412 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.25h; | /V,/V-Diisopropylethylamine (0.90 mL, 5.1 mmol) and maleimidoacetic acid /V-hydroxysuccinimide ester (141 mg, 0.561 mmol) were added sequentially to a room temperature solution of the product from Precursor Example 9, Step 3 (364 mg, 0.467 mmol) in dimethyl formamide (5 mL). LCMS indicated the reaction was complete within 15 minutes, whereupon the reaction was cooled to 0 C and the pH was adjusted to 1 by addition of 2,2,2-trifluoroacetic acid (0.432 mL, 6.6 mmol). Purification by preparative reverse phase HPLC and lyophilization gave the title compound (146 mg, 0.159 mmol, 34% yield). LCMS (Method b, Table 7) Rt= 0.79 min; MS m/z = 915.9 [M+H]+. 'H NMR (400 MHz, dimethylsulfoxide-d6) d 9.92 (s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.35 (d, / = 8.1 Hz, 3H), 7.28 (d, / = 10.1 Hz, 1H), 7.21 (d, J = 8.3 Hz, 3H), 7.16 (d, / = 7.9 Hz, 1H), 7.05 (s, 2H), 6.89 (d, / = 7.6 Hz, 1H), 6.13 (dd, / = 10.1, 1.9 Hz, 1H), 5.89 (d, J = 1.6 Hz, 1H), 5.44 (s, 1H), 4.93 - 4.83 (m, 2H), 4.80 (s, 1H), 4.53 (dd, / = 18.2, 8.2 Hz, 1H), 4.34 (td, / = 8.1, 5.3 Hz, 1H), 4.27 (s, 1H), 4.08 (s, 2H), 3.87 (s, 2H), 2.58 - 2.48 (m, 1H), 2.34 - 2.16 (m, 3H), 2.16 - 2.03 (m, 1H), 2.03 - 1.84 (m, 2H), 1.84 - 1.53 (m, 4H), 1.36 (s, 3H), 1.01 (td, J = 13.1, 11.3, 4.0 Hz, 2H), 0.84 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
120 mg | To compound 91 (230 mg, 0.15 mmol) in ethanol/water (10: 1, 15 mL) was added 10% palladium on carbon (41 mg, 0.04 mmol). The mixture was stirred under hydrogen at 30 psi in a Parr bomb. After 18 h, the reaction was filtered through a Ceiite pad, washed with EtOH/water (3: 1, 3x), concentrated, then dissolved in DMF (4 mL) and cooled in an ice/water bath. Tri ethyl amine (0 021 ml, 0.15 mmol) and 2,5-dioxopyrrolidin-l-yl 2-(2,5-dioxo-2,5- dihydro-lH-pyrrol-l-yl)acetate (38.2 mg, 0.15 mmol) were added sequentially and the reaction mixture was allowed to warm to room temperature. After 30 minutes, an aliquot (25 % by volume) was used directly in the next step. The remaining portion was purified by RP-HPLC (ISCO, 100 g column, 0-40 % ACN/water w/ 0.1 % 1 COOf 1 eluent) to afford compound 92 (120 mg, 58 % yield, 2 steps) as a white solid. ESI MS calc for C28H34N5O10 (M+H) 1391.6; found 1391.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Compound 117 (150 mg, 0 202 mmol), 2,5-dioxopyrrolidin-l-yl 2-(2,5-dioxo- (2210) 2,5-dihydro-lH-pyrrol-I-yl)acetate (51.1 mg, 0.202 mmol) and triethyiamine (0.028 ml, 0.202 mmol) in DCM (10 ml) were stirred at 0 C. After 1 hour DMF (1 ml) was added and the pH adjusted to pH 8-9 with triethyiamine. After 4 hours acetic acid (0.464 ml, 8.10 mmol) was added, the reaction mixture was concentrated and purified by RP-HPLC (acetonitrile/water buffered with 0.1% AcOH) to afford compound 118 as a white amorphous solid (56 mg, 32% yield) ESI MS calc for CseHeoNrOis (M+H) 878.40; found 878.37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | A mixture of N-{4-[6-oxo-1-(6-[N6-(26-oxo-2,5,8,11,14,17,20,23-octaoxahexacosan-26-yl)-L- lysyl]amino}hexyl)-5-(quinolin-5-yl)-1,6-dihydropyridazin-3-yl]phenyl}-1,3-dihydro-2H- pyrrolo[3,4-c]pyridine-2-carboxamide (see Intermediate 35-3, 30.0 mg, 26.3 mumol), maleimido acetic acid N-hydroxysuccinimide ester (7.30 mg, 29.0 mumol) and N,N-diisopropylethylamine (9.2 mul, 53 mumol) in DMF (0.55 mL) was stirred at r.t. for 30 min. Then the reaction was diluted with formic acid (2.0 mul, 53 mumol) in toluene (30 mL) and the mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO2, dichloromethane/isopropyl alcohol, gradient containing 10% DMSO) to give 5.14 mg (90% purity, 14% yield) of the title compound. (1315) LC-MS (Method 1): Rt = 0.81 min; MS (ESIpos): m/z = 610.8 [M+2H]2+, (ESIneg): m/z = 1218 [M-H]-. (1316) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.036 (0.20), 1.046 (0.20), 1.051 (0.20), 1.213 (0.20), 1.231 (0.27), 1.360 (0.73), 1.402 (0.46), 1.419 (0.40), 1.847 (0.33), 2.250 (0.40), 2.266 (0.86), 2.282 (0.40), 2.331 (1.20), 2.518 (6.77), 2.523 (4.38), 2.539 (15.20), 2.673 (1.20), 2.964 (0.27), 2.979 (0.40), 2.993 (0.33), 3.008 (0.27), 3.024 (0.27), 3.053 (0.27), 3.067 (0.20), 3.224 (6.51), 3.381 (0.13), 3.400 (0.60), 3.409 (1.00), 3.416 (0.73), 3.423 (1.20), 3.452 (1.59), 3.456 (1.66), 3.476 (6.51), 3.488 (16.00), 3.503 (0.73), 3.541 (0.53), 3.557 (1.00), 3.574 (0.46), 4.028 (0.20), 4.070 (0.80), 4.085 (0.73), 4.127 (0.27), 4.146 (0.20), 4.160 (0.20), 4.226 (0.33), 4.819 (0.80), 4.837 (0.80), 7.065 (3.72), 7.436 (0.46), 7.448 (0.46), 7.498 (0.40), 7.509 (0.40), 7.519 (0.40), 7.530 (0.40), 7.676 (0.40), 7.695 (0.53), 7.704 (0.93), 7.726 (1.00), 7.753 (0.20), 7.768 (0.33), 7.837 (0.40), 7.858 (0.46), 7.876 (0.40), 7.902 (1.20), 7.925 (0.93), 8.075 (0.40), 8.094 (0.40), 8.116 (0.53), 8.138 (0.46), 8.155 (1.39), 8.288 (0.40), 8.309 (0.33), 8.500 (0.66), 8.512 (0.60), 8.617 (0.93), 8.643 (0.73), 8.932 (0.46), 8.937 (0.46), 8.943 (0.46), 8.947 (0.40). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | A mixture of N-{4-[6-oxo-1-(6-[N6-(26-oxo-2,5,8,11,14,17,20,23-octaoxahexacosan-26-yl)-L- lysyl]amino}hexyl)-5-(quinolin-5-yl)-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H- pyrrolo[3,4-c]pyridine-2-carboxamide (41.2 mg, 36.1 mumol), 1-{2-[(2,5-dioxopyrrolidin-1- yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione (10.0 mg, 39.7 mumol) and N,N-diisopropylethylamine (13 mul, 72 mumol) in DMF (0.69 mL) was stirred at r.t. for 30 min under argon. Then the reaction was diluted with formic acid (2.7 mul, 72 mumol) in toluene (50 mL) and the mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO2, dichloromethane/isopropyl alcohol, gradient containing 10% DMSO) to give 8.7 mg (95% purity, 18% yield) of the title compound. (1343) LC-MS (Method 1): Rt = 0.83 min; MS (ESIneg): m/z = 1220 [M-H]-. (1344) 1H-NMR (400MHz, DMSO-d6) delta [ppm]: 1.13 - 1.28 (m, 3H), 1.28 - 1.50 (m, 8H), 1.55 - 1.75 (m, 3H), 2.27 (t, 2H), 2.94 - 3.09 (m, 4H), 3.23 (s, 3H), 3.26 - 3.30 (m, 1H), 3.36 - 3.44 (m, 4H), 3.44 - 3.52 (m, 26H), 3.56 (t, 2H), 3.77 - 3.89 (m, 2H), 4.08 (d, 2H), 4.11 - 4.19 (m, 1H), 4.74 - 4.85 (m, 5H), 7.07 (s, 2H), 7.42 - 7.48 (m, 2H), 7.56 (dd, 1H), 7.62 - 7.66 (m, 2H), 7.69 - 7.79 (m, 4H), 7.88 - 7.98 (m, 2H), 8.22 - 8.35 (m, 1H), 8.47 - 8.53 (m, 1H), 8.56 - 8.66 (m, 1H), 8.58 - 8.64 (m, 2H), 8.86 - 8.98 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | A mixture of N-(4-{5-[1-(6-aminohexyl)-1H-indazol-5-yl]-6-oxo-1-(2,2,2-trifluoroethyl)-1,6- dihydropyridazin-3-yl}phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (15.1 mg, 23.9 mumol), <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> (6.04 mg, 23.9 mumol) and N,N-diisopropylethylamine (8.3 mul, 48 mumol) in DMF (0.46 mL) was stirred at r.t. for 30 min under argon. Then formic acid (1.8 mul, 48 mumol) was added and the mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to give 5.35 mg (75% purity, 22% yield) of the title compound. (1405) HPLC: Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: YMC-Actus-ODS-AQ-HG-10mum 12nm 150x20mm; Eluent A: water + 0.1% fomic acid; Eluent B: acetonitrile; gradient: 0-14 min 15-55% B, 14-17 min 55-100% B; rate 60 mL/min, temperature 25C. LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 768[M+H]+. (1406) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.232 (2.04), 1.265 (1.41), 1.308 (1.21), 1.325 (1.45), 1.342 (1.45), 1.818 (1.21), 1.836 (1.58), 1.855 (1.12), 2.978 (0.79), 2.995 (1.95), 3.010 (2.04), 3.025 (0.91), 3.977 (8.10), 4.436 (1.54), 4.453 (2.95), 4.470 (1.41), 4.833 (3.66), 4.851 (3.53), 5.092 (0.71), 5.114 (1.75), 5.137 (1.66), 7.081 (16.00), 7.087 (1.00), 7.442 (1.91), 7.455 (1.91), 7.741 (4.11), 7.763 (4.82), 7.772 (2.20), 7.795 (2.20), 7.939 (4.95), 7.948 (2.91), 7.951 (2.74), 7.962 (4.11), 7.970 (1.91), 7.974 (1.70), 8.060 (0.66), 8.074 (1.21), 8.087 (0.66), 8.196 (5.03), 8.241 (5.36), 8.471 (3.16), 8.473 (3.24), 8.505 (2.12), 8.517 (1.95), 8.623 (3.16), 8.683 (3.32). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | A mixture of N-(4-{5-[2-(6-aminohexyl)-2H-indazol-5-yl]-6-oxo-1-(2,2,2-trifluoroethyl)-1,6- dihydropyridazin-3-yl}phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (11.8 mg, 18.7 mumol), <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> (4.72 mg, 18.7 mumol) and N,N-diisopropylethylamine (6.5 mul, 37 mumol) in DMF (0.36 mL) was stirred at r.t. for 30 min. Then formic acid (1.4 mul, 37 mumol) was added and the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 2.97 mg (75% purity, 16% yield) of the title compound. (1430) HPLC: Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: YMC-Actus-ODS-AQ-HG-10mum 12nm 150x20mm; Eluent A: water + 0.1% fomic acid; Eluent B: acetonitrile; gradient: 0-14 min 15-55% B, 14-17 min 55- 100% B; rate 60 mL/min, temperature 25C. (1431) LC-MS (Method 1): Rt = 0.95 min; MS (ESIpos): m/z = 768[M+H]+. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.231 (1.81), 1.256 (1.21), 1.270 (1.12), 1.292 (1.12), 1.328 (0.74), 1.352 (1.21), 1.366 (1.26), 1.910 (1.02), 1.928 (1.40), 1.946 (0.98), 2.995 (0.70), 3.012 (1.67), 3.026 (1.72), 3.042 (0.70), 3.984 (7.67), 4.433 (1.30), 4.451 (2.56), 4.468 (1.26), 4.833 (3.07), 4.851 (2.98), 5.086 (0.60), 5.109 (1.49), 5.131 (1.40), 5.154 (0.51), 7.087 (16.00), 7.442 (1.63), 7.456 (1.63), 7.674 (1.67), 7.697 (2.42), 7.739 (3.72), 7.762 (6.28), 7.766 (2.79), 7.785 (1.35), 7.789 (1.40), 7.935 (4.37), 7.957 (3.40), 7.972 (0.51), 8.072 (0.56), 8.086 (1.12), 8.100 (0.56), 8.208 (4.98), 8.482 (2.84), 8.505 (1.81), 8.517 (1.67), 8.552 (3.81), 8.623 (2.65), 8.682 (2.88). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | A mixture of N-(4-{5-[1-(6-aminohexyl)-1H-indazol-4-yl]-6-oxo-1-(2,2,2-trifluoroethyl)-1,6- dihydropyridazin-3-yl}phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (26.4 mg, 41.9 mumol), <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> (10.6 mg, 41.9 mumol) and N,N-diisopropylethylamine (15 muL, 84 mumol) in DMF (0.81 mL) was stirred at r.t. for 30 min under argon. Then formic acid (3.2 muL, 84 mumol) was added and the mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to give 5.70 mg (70% purity, 12% yield) of the title compound. (1461) HPLC: Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: YMC-Actus-ODS-AQ-HG 10mum 150x20mm; Eluent A: water + 0.1% fomic acid; Eluent B: acetonitrile; gradient: 0-14 min 15-55% B, 14-17 min 55-100% B; rate 60 mL/min, temperature 25C. (1462) LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 768[M+H]+. (1463) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.265 (3.47), 1.352 (2.12), 1.833 (2.03), 2.987 (1.10), 3.003 (2.54), 3.018 (2.54), 3.917 (1.19), 3.979 (8.72), 4.437 (1.95), 4.454 (3.47), 4.471 (1.69), 4.829 (4.06), 4.846 (3.81), 5.133 (2.12), 5.155 (2.03), 7.084 (14.81), 7.440 (2.12), 7.452 (2.12), 7.502 (6.10), 7.511 (3.47), 7.516 (3.56), 7.731 (4.40), 7.754 (4.91), 7.812 (1.61), 7.823 (1.52), 7.835 (1.27), 7.909 (5.08), 7.930 (3.98), 8.038 (5.33), 8.080 (1.44), 8.233 (5.67), 8.502 (1.95), 8.515 (1.78), 8.621 (3.13), 8.684 (3.39). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | A mixture of N-(4-{5-[2-(6-aminohexyl)-2H-indazol-4-yl]-6-oxo-1-(2,2,2-trifluoroethyl)-1,6- dihydropyridazin-3-yl}phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (11.3 mg, 17.9 mumol), <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> (4.52 mg, 17.9 mumol) and N,N-diisopropylethylamine (6.2 mul, 36 mumol) in DMF (0.34 mL) was stirred at r.t. for 30 min under argon. Then formic acid (1.4 mul, 36 mumol) was added and the mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to give 8.00 mg (65% purity, 38% yield) of the title compound. (1479) HPLC: Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: YMC-Actus-ODS-AQ-HG 10mum 150x20mm; Eluent A: water + 0.1% fomic acid; Eluent B: acetonitrile; gradient: 0-6 min 15-55% B, 6-8 min 55-100% B; rate 60 mL/min, temperature 25C. (1480) LC-MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 768[M+H]+. (1481) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.231 (1.99), 1.262 (2.33), 1.353 (1.24), 1.362 (1.24), 1.892 (1.10), 1.910 (1.37), 1.926 (0.96), 2.331 (2.88), 2.539 (1.24), 2.646 (0.41), 2.673 (2.88), 2.678 (1.24), 2.989 (0.82), 3.006 (1.79), 3.021 (1.72), 3.357 (0.48), 3.965 (7.55), 4.417 (1.44), 4.434 (2.33), 4.451 (1.17), 4.827 (3.09), 4.846 (2.75), 5.106 (0.76), 5.129 (1.72), 5.151 (1.51), 5.173 (0.48), 7.065 (16.00), 7.338 (1.51), 7.355 (1.85), 7.359 (1.51), 7.377 (1.79), 7.440 (1.65), 7.452 (1.65), 7.483 (2.47), 7.499 (1.92), 7.730 (3.85), 7.737 (2.95), 7.752 (4.05), 7.759 (2.20), 7.897 (4.12), 7.919 (2.95), 8.057 (0.62), 8.071 (1.10), 8.085 (0.55), 8.216 (5.01), 8.425 (3.57), 8.503 (2.06), 8.515 (1.85), 8.620 (2.88), 8.677 (2.61). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | A mixture of N-{4-[6-oxo-1-(6-[N6-(20-oxo-2,5,8,11,14,17-hexaoxaicosan-20-yl)-L-lysyl] amino}hexyl)-5-(quinolin-5-yl)-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo [3,4-c]pyridine-2-carboxamide (40.0 mg, 38.1 mumol), 1-{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2- oxoethyl}-1H-pyrrole-2,5-dione (10.6 mg, 42.0 mumol) and N,N-diisopropylethylamine (13 mul, 76 mumol) in DMF (0.73 mL) was stirred at r.t. for 30 min under argon. Then the reaction was diluted with formic acid (2.9 mul, 76 mumol) in toluene (50 mL) and the mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO2, dichloromethane/isopropyl alcohol, gradient containing 10% DMSO) to give 27.1 mg (95% purity, 60% yield) of the title compound. (1516) LC-MS (Method 1): Rt = 0.78 min; MS (ESIpos): m/z = 576.5 [M+2H]2+, (ESIneg): m/z = 1132 [M-H]-. (1517) 1H-NMR (400MHz, DMSO-d6) delta [ppm]: 1.17 - 1.28 (m, 3H), 1.28 - 1.49 (m, 10H), 1.59 (br s, 1H), 1.70 (br s, 2H), 2.27 (t, 2H), 2.33 - 2.34 (m, 1H), 2.52 - 2.54 (m, 10H), 2.67 - 2.68 (m, 1H), 2.69 - 2.70 (m, 1H), 2.94 - 3.09 (m, 4H), 3.22 (s, 3H), 3.36 - 3.58 (m, 24H), 3.75 - 3.90 (m, 2H), 4.03 - 4.19 (m, 3H), 4.74 - 4.74 (m, 1H), 4.74 - 4.85 (m, 4H), 7.02 - 7.12 (m, 1H), 7.07 (s, 1H), 7.42 - 7.47 (m, 2H), 7.52 - 7.59 (m, 1H), 7.62 - 7.66 (m, 2H), 7.69 - 7.79 (m, 4H), 7.89 - 7.98 (m, 2H), 8.27 - 8.35 (m, 1H), 8.46 - 8.52 (m, 1H), 8.58 - 8.64 (m, 3H), 8.92 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.166667h; | A mixture of N-{4-[1-(6-aminohexyl)-6-oxo-5-(quinolin-5-yl)-1,4,5,6-tetrahydropyridazin-3- yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (see Example 3, 23.5 mg, 95% purity, 39.7 mumol), <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> (10.0 mg, 39.7 mumol), and N,N-diisopropylethylamine (14 mul, 79 mumol) in DMF (760 mul) was stirred at r.t. for 10 min. Then toluene (50 mL) and formic acid (3.0 mul, 79 mumol) were added to the reaction solution and the mixture was concentrated under vacuum. The crude product was purified by Isolera (4 g 15 mum silicagel, eluent: dichloromethane/isopropyl alcohol, gradient) to give 22 mg of the desired product (95% purity, 74% yield). (1159) LC-MS (Method 1): Rt = 0.71 min; MS (ESIneg): m/z = 697 [M-H]- (1160) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.327 (1.76), 1.381 (0.69), 1.397 (0.81), 1.413 (0.54), 1.686 (0.57), 1.703 (0.75), 2.084 (0.57), 2.331 (0.96), 2.518 (6.39), 2.522 (3.85), 2.673 (0.96), 3.028 (1.10), 3.043 (1.10), 3.291 (0.51), 3.360 (0.90), 3.406 (0.57), 3.423 (0.66), 3.779 (0.63), 3.789 (0.63), 3.825 (0.87), 3.842 (0.87), 3.987 (5.19), 4.752 (0.48), 4.770 (0.63), 4.779 (0.66), 4.798 (2.24), 4.818 (1.91), 7.085 (9.19), 7.424 (1.04), 7.436 (1.16), 7.443 (1.07), 7.462 (1.07), 7.542 (0.87), 7.552 (0.90), 7.564 (0.90), 7.574 (0.90), 7.627 (1.76), 7.650 (2.72), 7.699 (0.93), 7.714 (2.93), 7.736 (1.94), 7.950 (1.25), 7.971 (1.01), 8.098 (0.81), 8.491 (1.40), 8.503 (1.31), 8.592 (0.93), 8.604 (2.18), 8.626 (1.85), 8.911 (1.04), 8.914 (1.07), 8.921 (1.10), 8.924 (0.96). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | A mixture of N-{4-[6-oxo-1-(6-[N6-(14-oxo-2,5,8,11-tetraoxatetradecan-14-yl)-L- lysyl]amino}hexyl)-5-(quinolin-5-yl)-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H- pyrrolo[3,4-c]pyridine-2-carboxamide (see Intermediate 42-3, 30.0 mg, 95% purity, 31.3 mumol), <strong>[55750-61-3]1-<strong>[55750-61-3]{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione</strong></strong> (8.69 mg, 34.4 mumol) and N,N-diisopropylethylamine (11 mul, 63 mumol) in DMF (600 mul) was stirred at r.t. for 30 min under argon. Then the reaction was diluted with formic acid (2.4 mul, 63 mumol) in toluene (50 mL) and the mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO2, dichloromethane/isopropyl alcohol, gradient containing 10% DMSO) to give 17.5 mg (95% purity, 51% yield) of the title compound. (1545) LC-MS (Method 1): Rt = 0.75 min; MS (ESIpos): m/z = 1046 [M+H]+, (ESIneg): m/z = 1044 [M-H]-. (1546) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.326 (0.55), 1.345 (0.32), 1.366 (0.21), 1.382 (0.20), 1.399 (0.21), 1.701 (0.19), 2.257 (0.27), 2.274 (0.60), 2.290 (0.28), 2.968 (0.18), 2.983 (0.26), 2.994 (0.30), 3.014 (0.19), 3.220 (4.94), 3.394 (0.34), 3.404 (0.65), 3.411 (0.51), 3.418 (0.78), 3.445 (0.30), 3.452 (0.66), 3.456 (1.10), 3.459 (1.14), 3.463 (0.70), 3.475 (5.06), 3.480 (0.67), 3.487 (0.62), 3.496 (0.30), 3.548 (0.32), 3.565 (0.70), 3.581 (0.31), 3.824 (0.20), 3.841 (0.19), 4.074 (0.50), 4.088 (0.49), 4.770 (0.17), 4.779 (0.17), 4.798 (0.57), 4.818 (0.48), 7.071 (2.48), 7.424 (0.28), 7.437 (0.30), 7.444 (0.26), 7.462 (0.28), 7.541 (0.24), 7.552 (0.24), 7.563 (0.24), 7.573 (0.24), 7.626 (0.48), 7.649 (0.70), 7.700 (0.26), 7.712 (0.76), 7.717 (0.45), 7.720 (0.39), 7.734 (0.45), 7.739 (0.31), 7.773 (0.22), 7.906 (0.22), 7.950 (0.33), 7.970 (0.26), 8.289 (0.24), 8.309 (0.23), 8.491 (0.37), 8.504 (0.34), 8.593 (0.24), 8.604 (0.56), 8.614 (0.26), 8.625 (0.47), 8.909 (0.29), 8.913 (0.30), 8.920 (0.28), 8.923 (0.25). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | mixture of N-{4-[6-oxo-1-(6-[N6-(20-oxo-2,5,8,11,14,17-hexaoxaicosan-20-yl)-L- lysyl]amino}hexyl)-5-(quinolin-7-yl)-1,6-dihydropyridazin-3-yl]phenyl}-1,3-dihydro-2H- pyrrolo[3,4-c]pyridine-2-carboxamide (21.0 mg, 20.1 mumol), 1-{2-[(2,5-dioxopyrrolidin-1- yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione (5.57 mg, 22.1 mumol) and N,N-diisopropylethylamine (7.0 mul, 40 mumol) in DMF (390 muL) was stirred at r.t. for 30 min under argon. Then the reaction was diluted with formic acid (1.5 mul, 40 mumol) in toluene (10 mL) and the mixture was concentrated under vacuum (azeotropic distillation with toluene was executed twice). The crude product was purified by column chromatography (SiO2, dichloromethane/isopropyl alcohol, gradient containing 10% DMSO) to give 8.90 mg (80% purity, 31% yield) of the title compound. (1593) LC-MS (Method 1): Rt =0.85 min; MS (ESIpos): m/z = 1131.8 [M+H]+. (1594) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.145 (0.30), 1.232 (0.74), 1.364 (0.89), 1.591 (0.15), 1.852 (0.30), 2.249 (0.44), 2.265 (0.74), 2.281 (0.44), 2.728 (1.78), 2.980 (0.44), 2.994 (0.30), 3.219 (5.19), 3.283 (0.44), 3.293 (0.59), 3.377 (1.19), 3.394 (0.74), 3.404 (1.04), 3.410 (0.89), 3.418 (1.33), 3.452 (2.22), 3.473 (5.93), 3.481 (10.81), 3.497 (0.59), 3.538 (0.44), 3.554 (0.89), 3.571 (0.30), 4.029 (0.15), 4.072 (0.59), 4.087 (0.59), 4.129 (0.15), 4.162 (0.30), 4.256 (0.44), 4.834 (0.74), 4.851 (0.59), 7.064 (2.96), 7.443 (0.30), 7.456 (0.30), 7.584 (0.44), 7.594 (0.44), 7.604 (0.30), 7.615 (0.44), 7.731 (0.74), 7.752 (1.04), 7.914 (0.30), 7.950 (0.44), 7.961 (0.89), 7.983 (0.59), 8.062 (0.44), 8.083 (0.59), 8.136 (0.44), 8.140 (0.44), 8.162 (0.30), 8.287 (0.30), 8.309 (0.30), 8.323 (1.04), 8.418 (0.30), 8.439 (0.30), 8.505 (0.44), 8.518 (0.44), 8.624 (0.74), 8.656 (0.59), 8.697 (0.59), 8.967 (0.44), 8.972 (0.44), 8.978 (0.44), 8.983 (0.30). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 14h; | A mixture of N-{4-[1-(6-aminohexyl)-6-oxo-5-(quinolin-7-yl)-1,4,5,6-tetrahydropyridazin-3- yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide hydrogen chloride (see Example 45, 15.0 mg, 23.6 mumol), maleimidoacetic acid N-hydroxysuccinimide ester (5.96 mg, 23.6 mumol), DIPEA (18 mul, 95 mumol) and DMF (360 muL) was stirred for 14 h at r.t.. After that the mixture was filtered and purified by preparative HPLC to give the title compound (8.00 mg, 48% yield). (1613) HPLC: Instrument: Labomatic HD-3000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 4000, Knauer UV detector Azura UVD 2.15, Prepcon 5 software. Column: Chromatorex C18 10muM 120x30 mm. Eluent A: water + 0.1 Vol-% HCOOH; Eluent B: acetonitrile; gradient: 0-20 min 10-50% B. rate 150 mL/min, temperature 25C. (1614) LC-MS (Method 1): Rt = 0.78 min; MS (ESpos): m/z = 699[M+H]+. (1615) H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.231 (0.55), 1.294 (3.40), 1.352 (1.24), 1.368 (1.38), 1.678 (1.33), 2.518 (11.22), 2.523 (7.45), 2.994 (0.83), 3.011 (1.89), 3.025 (1.89), 3.041 (0.74), 3.358 (0.69), 3.384 (1.24), 3.401 (1.10), 3.411 (1.10), 3.434 (1.10), 3.776 (0.46), 3.791 (0.74), 3.809 (1.38), 3.829 (1.33), 3.847 (0.69), 3.863 (0.41), 3.986 (8.92), 4.150 (0.87), 4.170 (1.33), 4.188 (0.74), 4.807 (3.22), 4.825 (3.13), 7.086 (16.00), 7.427 (1.75), 7.440 (1.75), 7.489 (1.93), 7.499 (1.89), 7.509 (1.84), 7.520 (1.89), 7.556 (1.52), 7.561 (1.56), 7.578 (1.56), 7.582 (1.61), 7.646 (3.31), 7.668 (4.46), 7.752 (4.55), 7.774 (2.90), 7.848 (2.76), 7.939 (2.71), 7.960 (2.34), 8.071 (0.69), 8.085 (1.33), 8.098 (0.64), 8.320 (1.47), 8.338 (1.33), 8.493 (2.34), 8.505 (2.11), 8.607 (3.31), 8.638 (2.94), 8.860 (2.02), 8.864 (2.07), 8.870 (1.93), 8.875 (1.75). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 14h; | A mixture of N-{6-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl)amino]phenyl}-6- oxo-5-(quinolin-7-yl)-5,6-dihydropyridazin-1(4H)-yl]hexyl}-D-asparagine (40.0 mg, 59.1 mumol), maleimidoacetic acid N-hydroxysuccinimide ester (14.9 mg, 59.1 mumol), DIPEA (31 mul, 180 mumol) and DMF (680 muL) was stirred for 14 h at r.t.. After that the mixture was filtered and purified by preparative HPLC to give the title compound (11.0 mg, 23% yield). (1631) HPLC: Instrument: Labomatic HD-3000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 4000, Knauer UV detector Azura UVD 2.15, Prepcon 5 software. Column: Chromatorex C18 10muM 120x20 mm. Eluent A: water; Eluent B: acetonitrile; gradient: 0-22 min 10-50% B. rate 50 mL/min, temperature 25C. (1632) LC-MS (Method 1): Rt = 0.73 min; MS (ESpos): m/z = 814[M+H]+. (1633) H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.228 (0.80), 1.304 (2.40), 1.349 (0.80), 1.369 (0.80), 1.683 (0.80), 2.518 (16.00), 2.523 (10.00), 2.539 (8.40), 2.674 (2.00), 2.727 (0.40), 2.886 (0.40), 3.002 (1.20), 3.017 (1.20), 3.793 (0.40), 3.810 (0.80), 3.829 (0.80), 3.845 (0.40), 4.043 (2.80), 4.048 (2.80), 4.143 (0.40), 4.163 (0.80), 4.182 (0.40), 4.477 (0.40), 4.803 (2.40), 4.821 (2.40), 7.064 (8.40), 7.426 (1.20), 7.438 (1.20), 7.487 (1.20), 7.497 (1.20), 7.508 (1.20), 7.518 (1.20), 7.551 (0.80), 7.555 (1.20), 7.572 (1.20), 7.577 (1.20), 7.635 (2.00), 7.658 (2.80), 7.742 (3.20), 7.764 (2.00), 7.841 (2.00), 7.939 (2.00), 7.960 (1.60), 8.319 (1.20), 8.337 (0.80), 8.429 (0.40), 8.489 (1.60), 8.501 (1.60), 8.603 (2.40), 8.647 (1.60), 8.855 (1.20), 8.859 (1.20), 8.865 (1.20), 8.870 (1.20). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 17h; | To a solution of L-valyl-N-{6-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl)amino]- phenyl}-6-oxo-5-(quinolin-7-yl)-5,6-dihydropyridazin-1(4H)-yl]hexyl}-L-alaninamide (6.66 mg, 9.09 mumol) in DMF (140 muL) was added at r.t. DIPEA (6.3 mul, 36 mumol) and 1-{2-[(2,5- dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione (2.52 mg, 10.0 mumol) and the mixture stirred for 14 h at that temperature. After that more 1-{2-[(2,5-dioxopyrrolidin-1- yl)oxy]-2-oxoethyl}-1H-pyrrole-2,5-dione (2.29 mg, 9.09 mumol) and DIPEA (27 mumol) were added and the mixture stirred for further 3 h. Then the mixture was filtered and purified by preparative HPLC to give the title compound (6.0 mg, 76% yield). (1665) HPLC: Instrument: Labomatic HD-3000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 4000, Knauer UV detector Azura UVD 2.15, Prepcon 5 software. Column: Chromatorex C18, 10 muM, 120x20 mm. Eluent A: water + 0.1 Vol-% formic acid; Eluent B: acetonitrile; gradient: 0-20 min 15-55% B. rate 50 mL/min, temperature 25C. (1666) LC-MS (Method 1): Rt = 0.80 min; MS (ESIpos): m/z = 870[M+H]+. (1667) H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.784 (1.83), 0.801 (1.89), 0.814 (1.89), 0.831 (1.89), 1.169 (2.02), 1.187 (2.02), 1.233 (0.43), 1.287 (1.10), 1.352 (0.61), 1.667 (0.43), 1.907 (0.43), 2.332 (2.50), 2.336 (1.16), 2.518 (16.00), 2.522 (10.32), 2.539 (0.73), 2.590 (0.61), 2.673 (2.63), 2.678 (1.16), 3.012 (0.49), 3.305 (0.55), 3.383 (0.43), 4.102 (1.95), 4.153 (0.49), 4.169 (0.79), 4.192 (0.55), 4.213 (0.55), 4.806 (0.98), 4.825 (0.98), 7.077 (6.47), 7.425 (0.55), 7.439 (0.55), 7.488 (0.73), 7.498 (0.67), 7.508 (0.67), 7.519 (0.73), 7.554 (0.49), 7.558 (0.55), 7.575 (0.49), 7.580 (0.55), 7.646 (1.04), 7.668 (1.47), 7.716 (0.55), 7.749 (1.53), 7.771 (0.98), 7.852 (0.85), 7.939 (0.92), 7.961 (0.79), 8.233 (0.49), 8.256 (0.49), 8.320 (0.49), 8.341 (0.49), 8.492 (0.79), 8.504 (0.79), 8.606 (1.10), 8.638 (0.98), 8.859 (0.67), 8.863 (0.73), 8.870 (0.73), 8.874 (0.67). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | A mixture of N-{4-[1-(6-aminohexyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-oxo-1,6-dihydro- pyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (see Example 10, 38.7 mg, 75.2 mumol), maleimido acetic acid N-hydroxysuccinimide ester (19.0 mg, 75.2 mumol) and N,N-diisopropylethylamine (26 mul, 150 mumol) in DMF (1.4 mL) was stirred at r.t. for 30 min. Then formic acid (5.7 mul, 150 mumol) was added to the reaction solution and the mixture was concentrated under vacuum. The crude product was purified by Isolera (4 g silicagel, (eluent: dichloromethane / isopropyl alcohol) to give 19.4 mg (93% purity, 37% yield) of the desired product. (1265) LC-MS (Method 1): Rt = 0.70 min; MS (ESIneg): m/z = 650[M-H]- (1266) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.026 (15.89), 1.042 (16.00), 1.239 (2.40), 1.255 (2.11), 1.269 (1.42), 1.345 (2.29), 1.387 (1.05), 1.401 (1.11), 1.418 (0.69), 1.799 (0.76), 1.817 (1.00), 1.832 (0.69), 2.331 (1.08), 2.518 (5.67), 2.523 (3.80), 2.627 (15.60), 2.673 (1.13), 3.013 (0.63), 3.030 (1.48), 3.044 (1.48), 3.060 (0.55), 3.984 (7.06), 4.213 (0.98), 4.231 (1.58), 4.248 (0.92), 4.830 (2.43), 4.847 (2.40), 7.082 (12.73), 7.135 (0.47), 7.443 (1.29), 7.456 (1.29), 7.735 (2.77), 7.757 (3.43), 7.875 (3.64), 7.897 (2.56), 8.087 (0.53), 8.101 (1.03), 8.113 (0.53), 8.505 (1.56), 8.511 (5.38), 8.623 (2.03), 8.682 (2.37). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | mixture of N-{4-[1-(6-aminohexyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-oxo-1,4,5,6- tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (see Example 11, 7.60 mg, 14.7 mumol), maleimido acetic acid N-hydroxysuccinimide ester (3.71 mg, 14.7 mumol) and N,N-diisopropylethylamine (5.1 mul, 29 mumol) in DMF (280 mul) was stirred at r.t. for 30 min. Then formic acid (1.1 mul, 29 mumol) was added to the reaction solution and the mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO2, eluent: dichloromethane / isopropyl alcohol) to give 2.2 mg of the desired product (80% purity, 18% yield). (1255) LC-MS (Method 1): Rt = 0.75 min; MS (ESIpos): m/z = 654 [M+H]+ (1256) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.026 (8.25), 1.040 (8.13), 1.233 (16.00), 1.272 (14.10), 1.349 (7.75), 1.474 (5.46), 1.629 (4.83), 2.326 (9.65), 2.625 (11.05), 2.668 (10.67), 3.029 (7.24), 3.465 (3.30), 3.751 (6.10), 3.982 (14.60), 4.834 (12.95), 5.759 (5.33), 7.083 (15.11), 7.446 (4.83), 7.691 (8.00), 7.735 (9.65), 7.756 (6.98), 7.876 (2.54), 8.092 (3.94), 8.511 (6.48), 8.618 (6.22), 8.665 (5.46). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;Inert atmosphere; | Compound 103 (35 mg, 0.024 mmol) and maleimidoacetic acid N-hydroxysuccinimide ester (9 mg, 0.035 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and then N,N-diisopropylethylamine (0.021 mL, 0.23 mmol) was added thereto at 0C under a nitrogen atmosphere. The reaction temperature was gradually raised to room temperature and then the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, then purified by HPLC, and freeze-dried to obtain Compound 104 (15.1 mg, 37%) as a white solid. EI-MS m/z : [M+H]+ 1612.6, 1/2[M+H]+ 807.2. |
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