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CAS No. : | 1342211-31-7 | MDL No. : | MFCD27956998 |
Formula : | C18H27N3O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GSWKJIWKGSPISH-LRDDRELGSA-N |
M.W : | 381.42 | Pubchem ID : | 67452206 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
97% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; | 150 mg (0.797 mmol) of <strong>[1115-74-8]L-valyl-L-alanine</strong> and 246 mg (0.797 mmol) of 1-{6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexyl}-1H-pyrrole-2,5-dione were dissolved in 4.0 ml of dimethylformamide, and 0.220 ml (1.6 mmol) of triethylamine was added. The reaction mixture was stirred at RT overnight. The reaction mixture was purified directly by preparative RP-HPLC (column: Reprosil 250*30; 10mu, flow rate; 50 ml/min, MeCN/water). The solvents were evaporated under reduced pressure and the residue was dried under high vacuum. This gave 302 mg (97% of theory) of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) hexanoyl]-<strong>[1115-74-8]L-valyl-L-alanine</strong>. LC-MS (Method 12): Rt=1.02 min; MS (ESIpos): m/z=382 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=0.82 (dd, 6H), 1.17 (m, 2H), 1.27 (d, 3H), 1.48 (m, 4H), 1.94 (m, 1H), 2.13 (m, 2H), 3.38 (t, 2H), 4.17 (m, 2H), 7.00 (s, 2H), 7.75 (d, 1H), 8.19 (d, 1H). |
70% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Maeilimidocaproy. N-hydroxysuccinimide (1.619 g, 5.25 mmo., 105 eq.) and H-Val-Aia-OH (0,941 g, 5 mmol, 1 eq.) were placed in a 25 ml recovery fiask with a stir bar and the flask was flushed with nitrogen, DMF (4,7 mL) was added and the resulting white siurry was stirred. DIPEA (0.87 mL, 5 mmol, 1 eq) was added and the mixture was allowed to stir at room temperature overnight. The mixture was coo.ed in an ice/water bath and 2M HCI (3 mL, 6 mmol) was added dropwise. The viscous mixture was transferred to a separator/ funnel and the reaction vessel rinsed with sat. NaCl (7 mL), EtOAc (10 mL), sat NaCl {10 mL) and EtOAc (5 mL). After separation of the aqueous phase, it was extracted with additionai EtOAc {2 x 15 mL). The combined organic extracts were washed with sat NaCi {4 x 15 mL), until the washings were pH ~3,5. The organic extracts were dried over Na2S04, filtered and concentrated under reduced pressure to give crude 5 as a white solid (2,1 2 g, 114% crude yield). Crude 5 was suspended in warm CHjCIa {35 mL) and filtered to remov a fine white solid. The solids wer rinsed with additional CHjCi2 (3 mL). Toiuene {5mL) was added and the mixture was cooled in an ice/water bath, which resulted in a thick siurry. The solids were collected by filtration, washed with a cold mixture of CHjC (12 mL) and toluene (2 mL) and dried by puiilng air through the sample overnight to give 5 as a White solid (1 ,327 g, 70% yield). TLC: Rf = 0.26, 10% MeOH in CH2CI2. 1 H NMR (CDCI3)(ppm) 0.95 {d, J - 17 Hz, 3H), 0.98 (d, J - 17 Hz, 3H), 1.30 (m, 2H), 1.40 (d, J = 17 Hz, 3H), 1.61 (m, 4H), 2.06 (m, 1 H), 2.25 (dt, J = 4, 19 Hz, 2H). 3.35 (s, 1 H), 3.49 (t, J - 17 Hz,2H), 4.20 (d, J = 18 Hz, 1 H), 4.38 (m, 1 H), 6.80 {s, 2H). Analytical HPLC (0.1% formic acid): tR 9.05 min. LC-MS: tR 11.17 min, m/z (ES+) found 381.9 (M+H)+, m/z (ES-) found 379.9 (M-H)-. |
52% | In N,N-dimethyl-formamide; at 20℃; for 48h; | (a) (S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3- methylbutanamido)propanoic acid (23)A suspension of dipeptide (22) (0.1 g, 0.54 mmol, 1 eq.) and 6-maleimidohexanoic acid succinimide ester (0.165 g, 0.54 mmol, 1 eq.) in anhydrous DMF (5 mL) was stirred at room temperature for 24 hours at which time LCMS indicated 50% conversion to a new product. The reaction mixture was diluted with anhydrous DMF (5 mL) and the reaction was allowed to continue for a further 24 hours. The solvent was evaporated under reduced pressure to give a colourless residue. Diethyl ether (60 mL) was added and the mixture was sonicated for 5 min, the ether was decanted and the process was repeated (x 2). The final ethereal portion was filtered to isolate the product (23) as a white powder which was dried under vacuum (0.105 g, 52%). Analytical Data: RT 2.28 min; MS (ES+) m/z (relative intensity) 382 ([M + H]+ , 90), MS (ES") m/z (relative intensity) 380 ([M - H])-, 100). |
With triethylamine; | 150 mg (0.797 mmol) of <strong>[1115-74-8]L-valyl-L-alanine</strong> and 246 mg (0.797 mmol) of 1-{6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexyl}-1H-pyrrole-2,5-dione were dissolved in 4.0 ml of dimethylformamide, and 0.220 ml (1.6 mmol) of triethylamine were added. The reaction mixture was stirred at RT overnight. The reaction mixture was purified directly by preparative RP-HPLC (column: Reprosil 250*30; 10mu, flow rate: 50 ml/min, MeCN/water). The solvents were evaporated under reduced pressure and the residue was dried under high vacuum. This gave 302 mg (97% of theory) of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-<strong>[1115-74-8]L-valyl-L-alanine</strong>. LC-MS (Method 12): Rt=1.02 min; MS (ESIpos): m/z=382 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=0.82 (dd, 6H), 1.17 (m, 2H), 1.27 (d, 3H), 1.48 (m, 4H), 1.94 (m, 1H), 2.13 (m, 2H), 3.38 (t, 2H), 4.17 (m, 2H), 7.00 (s, 2H), 7.75 (d, 1H), 8.19 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: (S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-hexanamido)-3-methylbutanamido)propanoic acid With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 0.25h; Inert atmosphere; Stage #2: (S)-2-(4-aminophenyl)-7-methoxy-8-(3-((S)-7-methoxy-2-methyl-5-oxo-5,11a-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-8-yloxy)propoxy)-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5(11aH)-one In methanol; dichloromethane at 20℃; for 3h; Inert atmosphere; | 7.a (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-((4-^methoxy-2-methyl-5-oxo-5, 11 a-dihydro-1 H-pyrrolo[2, 1-c][1 ,4]benzodiazepin-8- yl)oxy)propoxy)-5-oxo-5, 11 a-dihydro-1 H-pyrrolo[2, 1 -c][1 ,4]benzodiazepin-2- yl)phenyl)amino)- 1-oxopropan-2-yl)amino)-3-methyl- 1-oxobutan-2-yl)hexanamide (30) To a mixture of carboxylic acid 23 (8 mg, 21 umol) in 5% methanol/dichloromethane was added EEDQ (6.1 mg, 24.6 umol) and the mixture was stirred for 15 minutes under nitrogen at an ambient temperature. The resulting mixture was added to 1 1 (12 mg, 18.9 umol) and stirred for 3 hours under nitrogen. The reaction mixture was aspirated directly onto a 1 mm radial chromatotron plate and eluted with a gradient of 1 to 4% methanol in dichloromethane. Product containing fractions were concentrated under reduced pressure to give 9.4 mg (50%) of 30 as a yellow solid: MS (ES") m/z 997.18 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 23h; Inert atmosphere; | 4.ii.b (b) 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1^methoxy-5-oxo-2-((E)-styryl)-5, 11a-dihydro-pyrrolo[2, 1-c][1,4]benzodiazepin-8- yl)oxy)propoxy)-5-oxo-5, 11a-dihydro-pyrrolo[2, 1-c][1,4]benzodiazepin-2-yl)phenyl)amino)- 1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide (24)The unsymmetrical PBD dimer (21 ) (0.019 g, 26 μιηοΙ, 1 eq.) was added to a solution of the linker (23) (0.0121 g, 31 .6 μιηοΙ, 1 .2 eq.) and EEDQ (0.0098 g, 39.6 μιηοΙ, 1 .5 eq.) in a mixture of anhydrous DCM/MeOH (3 mL/0.5 mL) under an argon atmosphere. The resultant solution was stirred at room temperature for 5 hours at which time LCMS indicated 50% conversion to a new product. The reaction mixture was diluted with anhydrous DCM (2 mL) and the reaction was allowed to continue for a further 18 hours. The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography [DCM 100% to DCM 94%/MeOH 6% in 1 % increments] to give the product as a yellow solid (5.2 mg, 18%). Analytical Data: RT 3.10 min; MS (ES+) m/z (relative intensity) 1085 ([M + H]+ , 90). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Stage #1: (S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-hexanamido)-3-methylbutanamido)propanoic acid With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane for 0.25h; Inert atmosphere; Stage #2: (S)-2-(4-aminophenyl)-7-methoxy-8-(5-((S)-7-methoxy-2-(4-methoxycarbonylphenyl)-5-oxo-5,11a-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yloxy)pentyloxy)-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5(11aH)-one In methanol; dichloromethane at 20℃; for 4h; Inert atmosphere; | 2.b methyl 4-((S)-8-((5-(((S)-2-(4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)phenyl)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-2-yl)benzoate A 10 ml flask was charged with 5 (11 mg, 29 pmoi), EEDQ (8.9 mg, 38 Mmol), and; 0.46 mL anhydrous CHsC.j. Methanol (24 ul.) was added to facilitate dissolution and the mixture was stirred under nitrogen for 15 min. Aniiine 4 (18 ting , 24 μη οί) was then added and the reaction mixture was stirred at room temperature for 4 hours, at which time LC-MS revealed conversion to product. The reaction was concentrated, dissolved In CH2C12 (1 mL) and purified by radia. chromatography on a 1 mm chromatotron plate e.uted with CHaCia/ CH3OH mixtures (100:0 to 90:10 CH23OH) to provide 6 (9.9 mg, 36%). Analytical HPLC: tR 12.10 mm, LC-MS: tR 12.91 min, m/z (ES+) found 1145.6 (M +H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: (S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-hexanamido)-3-methylbutanamido)propanoic acid With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 0.25h; Inert atmosphere; Stage #2: (S)-2-(4-aminophenyl)-8-(3-(((S)-2-(4-hydroxyphenyl)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)propoxy)-7-methoxy-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one In methanol; dichloromethane at 20℃; for 4h; Inert atmosphere; | 5 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)N-((S)-1-(((S)-1-((4-((S)-8-(3-(((S)-2-(4-hydroxyphenyl)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)propoxy)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-2-yl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide A flame-dried flask was charged with maieimidocaproyl-valine-aianine linker (Compound 36 of Example 13 in WO 2011/130613 A ) (11 mg, 29 pmoS, 1,5 eq) dissolved in 0,8 mL of 5% methanol in anhydrous dichioromethane. The acid was pre-activated by addition of N- ethoxycarbonyi-2-ethoxy-1 ,2-dihydroquinoline (9 mg, 34 moL 1.8 eq), followed by stirring at room temperature under nitrogen for 15 minutes. The activated acid was then to a flame-dried flask containing PBD dimer 14 (13 mg, 19 prnoi, 1 eq). The reaction was stirred for 4 hours at room temperature under nitrogen, at which time LC-MS revealed conversion to product. The materia. was diluted in dichloromethane and purified by radial chromatography on a 1 mm ehromafotron plate e.uted with CH2Cl2/MeOH mixtures {100:0 to 80:20) to provide 15 (7.7 mg, 38%). LC- S: ffl/z (ES' ) found 1075.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: (S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-hexanamido)-3-methylbutanamido)propanoic acid With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane for 0.5h; Stage #2: (S)-2-(4-aminophenyl)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)propoxy)-1,11a-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5-one In methanol; dichloromethane at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | Stage #1: (S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-hexanamido)-3-methylbutanamido)propanoic acid With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 0.25h; Inert atmosphere; Stage #2: (S)-2-(4-aminophenyl)-8-((5-(((S)-2-(4-(3-(dimethylamino)propoxy)phenyl)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-7-methoxy-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one In methanol; dichloromethane at 20℃; for 7h; Inert atmosphere; | 7 N-((S)-1-(((S)-1-((4-((S)-8-((5-(((S)-2-(4-(3-(dimethylamino)propoxy)phenyl)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yI)oxy)pentyl)oxy)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-2-yI)phenyl)amino)-1-oxobutan-2-yI)amino)-3-methyl-1-oxobutan-2-yI)-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamide (19) A flame-dried flask was charged with maleimidocaproyl-valine-afanine linker (Compound 36 in Example 3 of WO 2011/130613 A1 ) (9 mg, 24 pmol, 1.5 eq) dissolved in 0.33 mL of 5% methanol in anhy drous dichloromethane. The acid was pre-activated by addition of N- ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (7.1 mg, 29 μmol, 1.8 eq), followed by stirring at room temperature under nitrogen for 15 minutes. The activated acid was then added to a flame-dried flask containing PBD dimer 17 (13 mg, 16 μmol, 1 eq). The reaction was stirred for 7 h at room temperature under nitrogen, at which time LC-MS revealed conversion to product. The material was diluted in dichloromethane and purified by radial chromatography on a 1 mm chromatotron plate eluted with CH2Cl2/MeOH mixtures (100:0 to 80:20) to provide 19 (5.1 mg, 27%). LC-MS: to 9.09 min. m/z (ES+) found 1188.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: (S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-hexanamido)-3-methylbutanamido)propanoic acid With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 0℃; for 0.25h; Stage #2: (R)-2-(4-(2,5,8,11-tetraoxatridecan-13-yloxy)phenyl)-8-((5-(((R)-2-(4-aminophenyl)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-7-methoxy-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one In methanol; dichloromethane for 3h; | 8.d (d) N-((S)-1-(((S)-1-((4-((R)-8-((5-(((R)-2-(4-(2,5,8,11-tetraoxatridecan-13-yloxy)phenyl)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-7-methoxy-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-2-yl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamide (24) To a mixture of the mc-val-ala-OH (50 mg, 0.129 mmol) in 5% methanol in dichloromethane (1 mL) at 0°C was added EEDQ (32 mg, 0.129 mmol). The mixture was stirred for 15 min, and then a solution of the aniline (44 mg, 0.044 mmol) in 5% methanol in dichloromethane (1 mL) was added. The reaction mixture was allowed to stir for 3 hours, was diluted with dichloromethane (2 mL) and was aspirated directly onto a 2 mm radial chromatotron plate. The product was eluted with a gradient of 2.5 % to 5% methanol in dichloromethane to give 22.5 mg (40%): LC-MS: m/z (ES+) found 1294 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 20 °C 2: triphenylphosphine; N-Bromosuccinimide / tetrahydrofuran / 7 h / 20 °C / Sonication |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 20 °C 2: triphenylphosphine; N-Bromosuccinimide / tetrahydrofuran / 7 h / 20 °C / Sonication 3: N,N-dimethyl-formamide / 1.5 h / 45 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; | 6 Example 6. 6-(2, 5-dioxo-2, 5-dihydro-]H-pyrrol-] -yl)-N-((S)-] -(((S)-] -((4- (hydroxymethyl)phenyl)amino)-] -oxopropan-2-yl)amino)-3-methyl-] -oxobutan-2-yl)hexanamide (6): Added (6-(2,5 -dioxo-2,5 -dihydro- 1 H-pyrrol- 1 -yl)hexanoyl)-L-valyl-L-alanine (500 mg, 1.31 mmol) and (4-aminophenyl)methanol (170 mg, 1.38 mmol) into a round bottom flask. Added anhydrous DCM (5 mL) and anhydrous MeOH (500 pL) and stirred to dissolve solids. EEDQ (357 mg, 1.44 mmol) was added and thereaction stirred at room temperature overnight. Reaction solvents were removed undervacuum and the crude material purified by silica gel chromatography (3-10% MeOHin DCM) to provide the title compound (579 mg, 91%). LCMS: tR = 0.95 mm; mlz =973.7 [M+H1. ‘H NMR (400 MHz, Methanol-d4 + CDC13) ö 7.59 -7.51 (m, 2H),7.33 -7.25 (m, 2H), 6.78 (s, 2H), 4.56 (s, 2H), 4.48 (q, J = 7.1 Hz, 1H), 4.16 (d, J =7.2 Hz, 1H), 3.48 (t, J = 7.1 Hz, 2H), 2.32 -2.21 (m, 2H), 2.17 -2.00 (m, J = 6.7 Hz,1H), 1.70- 1.52 (m, 4H), 1.44 (d, J = 7.1 Hz, 3H), 1.37 - 1.24 (m, 2H), 0.98 (d, J =6.8 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C | ||
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane | 130 mg (0.531 mmol) of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-L-alanine were dissolved in 6.5 ml of dichloromethane, and 58.8 mg (0.511 mmol) of 1-hydroxypyrrolidine-2,5-dione and 78.4 mg (0.409 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. Another 58.8 mg (0.511 mmol) of 1-hydroxypyrrolidine-2,5-dione and 78.4 mg (0.409 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. Dichloromethane was added and the mixture was washed three times with water. The organic phase was dried over magnesium sulphate, the solvent was evaporated under reduced pressure and the residue was dried under high vacuum. This gave 172 mg (87% of theory) of the title compound. LC-MS (Method 12): Rt=1.28 min; MS (ESIpos): m/z=479 (M+H)+. |
87% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane | Intermediate L88 130 mg (0.531 mmol) of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-L-alanine were dissolved in 6.5 ml of dichloromethane, and 58.8 mg (0.511 mmol) of 1-hydroxypyrrolidine-2,5-dione and 78.4 mg (0.409 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. Another 58.8 mg (0.511 mmol) of 1-hydroxypyrrolidine-2,5-dione and 78.4 mg (0.409 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. Dichloromethane was added and the mixture was washed three times with water. The organic phase was dried over magnesium sulphate, the solvent was evaporated under reduced pressure and the residue was dried under high vacuum. This gave 172 mg (87% of theory) of the title compound. [1079] LC-MS (Method 12): R4=1.28 min; MS (ESIpos): m/z=479 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In N,N-dimethyl-formamide at -78 - 20℃; for 3h; | Allyl (6aS)-3-(4-((5-((4-(5-((4-(CS)-2-(CS)-2-((((9if-fluoren-9-yl)methoxy)- carbonyl)amino)-3-methylbutanamido)propanamido)phenyl)carbamoyl)- i-methyl-iff-pyrrol-3-yl)phenyl)carbamoyl)-i-methyl-iJi-pyrrol-3- yl)amino)-4-oxobutoxy)-2-methoxy-i2-oxo-6-((tetrahydro-2ii-pyran-2- yl)oxy)-6, 6a, 7,8,9, io-hexahydrobenzo[e]pyrido[i,2-a][i,4]diazepine- 5(i2/ To a stirred solution of allyl (6aS')-3-(4-((5-((4-(5-((4-aminophenyl)carbamoyl)-i- methyl-iff-pyrrol-3-yl)phenyl)carbamoyl)-i-methyl-iff-pyrrol-3-yl)amino)-4- oxobutoxy)-2-methoxy-i2-oxo-6-((tetrahydro-2 7-pyran-2-yl)oxy)-6,6a,7,8,9,io- hexahydrobenzo[e]pyrido[i,2-a][i,4]diazepine-5(i2ff)-carboxylate (14) (870 mg, 0.923 mmol) and (((9H-fluoren-9-yl)methoxy)carbonyl)-L-valyl-L-alanine (450 mg, 1.10 mmol) in methanol / dichloromethane (10 mL, 1:10 v/v), was added N- ethoxycarbonyl-2-ethoxy-i,2-dihydroquinoline (340 mg, 1.37 mmol) at room temperature. The reaction mixture was stirred for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography (silica), eluting with methanol / dichloromethane (isocratic 5%), to give the title compound (860 mg, 70%) as a cream solid. MS (ES+): m/z = 1335.9 (M+H)+; LCMS (Method B): tR = 4.20 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3: zinc(II) chloride / 2,2,2-trifluoroethanol / 2 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3: zinc(II) chloride / 2,2,2-trifluoroethanol / 1 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere 4: zinc(II) chloride / 2,2,2-trifluoroethanol / 2 h / 50 °C 5: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere 4: zinc(II) chloride / 2,2,2-trifluoroethanol / 2 h / 50 °C 5: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere 6: zinc(II) chloride / 2,2,2-trifluoroethanol / 2 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere 5: zinc(II) chloride / 2,2,2-trifluoroethanol / 2 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere 4: zinc(II) chloride / 2,2,2-trifluoroethanol / 2 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere 4: zinc(II) chloride / 2,2,2-trifluoroethanol / 2 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 14h; | N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[(4R)-3-{4-[(1,3-dihydro-2H- pyrrolo[3,4-c]pyridin-2-ylcarbonyl)amino]phenyl}-6-oxo-4-phenyl-5,6-dihydropyridazin-1(4H)- yl]butyl}-L-alaninamide A mixture of N-{4-[(4R)-1-(4-aminobutyl)-6-oxo-4-phenyl-1,4,5,6-tetrahydropyridazin-3- yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (180 mg, 60 % purity, 224 mol), N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-L-alanine (85.4 mg, 224 mol), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro- phosphate) (HATU, 85.1 mg, 224 mol), N-methylmorpholine (62 l, 560 mol) and DMF (4.5 mL) was stirred at r.t. for 14 h. After that the mixture was filtered and the filtrate was purified by preparative HPLC to give the title compound (34.0 mg, 17% yield). 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 10M 125x30 mm. Eluent A: water + 0.1% HCOOH; Eluent B: acetonitrile; gradient: 0-8, min 15-55% B. rate 60 ml/min, temperature 25°C. LC-MS (method 1): Rt = 1.02 min; MS (ESIpos): m/z = 846 [M+H]+ H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.785 (4.88), 0.802 (5.35), 0.812 (4.79), 0.829 (4.88), 0.857 (0.68), 1.147 (1.37), 1.168 (4.28), 1.174 (4.06), 1.186 (4.32), 1.192 (3.76), 1.232 (0.60), 1.356 (0.90), 1.375 (1.45), 1.394 (1.33), 1.413 (0.77), 1.429 (1.07), 1.448 (2.10), 1.467 (2.65), 1.484 (2.05), 1.604 (0.77), 1.622 (1.11), 1.640 (1.03), 1.656 (0.68), 1.723 (0.60), 1.919 (0.51), 1.935 (0.77), 1.952 (0.77), 1.969 (0.47), 2.075 (0.51), 2.093 (0.81), 2.111 (1.07), 2.128 (1.03), 2.146 (1.07), 2.164 (0.68), 2.181 (0.47), 2.518 (16.00), 2.523 (10.95), 2.540 (3.34), 2.549 (1.63), 2.590 (1.37), 3.006 (0.43), 3.025 (0.60), 3.043 (1.28), 3.062 (1.58), 3.083 (1.41), 3.103 (1.24), 3.217 (0.56), 3.341 (2.48), 3.359 (4.15), 3.377 (2.87), 3.449 (2.18), 3.647 (0.68), 3.664 (0.81), 3.680 (0.81), 3.693 (0.77), 3.819 (0.64), 3.831 (0.68), 3.852 (0.64), 3.863 (0.51), 4.103 (0.90), 4.120 (1.11), 4.124 (1.11), 4.141 (0.98), 4.198 (0.94), 4.216 (1.33), 4.234 (0.90), 4.686 (1.20), 4.705 (1.20), 4.863 (4.92), 6.977 (0.81), 6.992 (13.90), 7.153 (2.57), 7.171 (3.34), 7.215 (0.77), 7.233 (1.80), 7.252 (1.24), 7.296 (2.57), 7.316 (3.25), 7.334 (1.28), 7.429 (0.81), 7.590 (3.42), 7.612 (4.62), 7.644 (0.98), 7.657 (0.98), 7.693 (4.32), 7.716 (2.87), 7.783 (1.41), 7.809 (1.45), 7.908 (0.94), 7.926 (0.94), 8.608 (1.63), 8.621 (1.45), 8.669 (2.70), 8.728 (2.31). |