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CAS No. : | 870487-09-5 | MDL No. : | MFCD22200277 |
Formula : | C23H37N5O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VYCVAPFXSOAOCL-ROUUACIJSA-N |
M.W : | 479.57 | Pubchem ID : | 59841854 |
Synonyms : |
Boc-Val-Cit-PABA
|
Num. heavy atoms : | 34 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.57 |
Num. rotatable bonds : | 17 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 6.0 |
Molar Refractivity : | 127.79 |
TPSA : | 171.88 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.41 cm/s |
Log Po/w (iLOGP) : | 2.13 |
Log Po/w (XLOGP3) : | 1.15 |
Log Po/w (WLOGP) : | 1.26 |
Log Po/w (MLOGP) : | 0.68 |
Log Po/w (SILICOS-IT) : | 1.24 |
Consensus Log Po/w : | 1.29 |
Lipinski : | 2.0 |
Ghose : | None |
Veber : | 2.0 |
Egan : | 1.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.17 |
Log S (ESOL) : | -2.55 |
Solubility : | 1.36 mg/ml ; 0.00284 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.35 |
Solubility : | 0.0212 mg/ml ; 0.0000443 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.8 |
Solubility : | 0.0076 mg/ml ; 0.0000158 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.22 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | 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 |
---|---|---|
78.06% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 25℃; for 8h;Darkness; | To a solution of Compound 2 (7.00 g, 18.70 mmol, 1.00 eq) in DCM (80.00 mL) and MeOH (40.00 mL) was added (4-aminophenyl)methanol (2.53 g, 20.56 mmol, 1.10 eq) and EEDQ (9.25 g, 37.39 mmol, 2.00 eq) in the dark. And the mixture was stirred at 25 C for 8 hr. LC-MS showed Compound 2 was consumed completely and one main peak with desired MS was detected. The resulting reaction mixture was concentrated under reduced pressure to remove the solvent to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 120 g SepaFlash Silica Flash Column, Eluent of 0-10% MeOH/DCM 85 mL/min). Compound 3 (7.00 g, 14.60 mmol, 78.06% yield) was obtained as a white solid. |
78.06% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 25℃; for 8h;Darkness; | General procedure: To a solution of Compound 2 (7.00 g, 18.70 mmol, 1.00 eq) in DCM (80.00 mL) and MeOH (40.00 mL) was added (4-aminophenyl)methanol (2.53 g, 20.56 mmol, 1.10 eq) and EEDQ (9.25 g, 37.39 mmol, 2.00 eq) in the dark. And the mixture was stirred at 25 C for 8 hr. LC-MS showed Compound2 was consumed completely and one main peak with desired MS was detected. The resulting reaction mixture was concentrated under reduced pressure to remove the solvent to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 120 g SepaFlash Silica Flash Colunm, Eluent of 0-40% MeOH/DCM 85 mL/min). Compound 3 (7.00 g, 14.60 mmol, 78.06% yield) was obtained as a white solid. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane;Darkness; | Compound E- 11-4: tert-butyl ((5)-i -(((5)-i -((4-(hydroxymethyl)phenyl) amino)- 1 -oxo-5-ureidopentan-2-yl)amino)-3 -methyl-i -oxobutan-2-yl)carbamate Compound E-11-3 (5g, 13.4 mmol, 1 eq.) was dissolved in a mixture of dry DCM (65 ml) and dry MeOH (35 ml). (4-aminophenyl)methanol (1.81 g, 14.7 mmol,1.1 eq.) and N-Ethoxycarbonyl-2-ethoxy-i,2-dihydroquinoline (EEDQ - 6.60 g, 26.7 mmol, 2 eq.) were added and the mixture stirred in the dark overnight. The solventswere evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 5.2 g (73 %) of compound E-11-4 as an off-white solid. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane;Darkness; | Compound E-ll-4: tert-butyl ((5)-l-(((5)-l-((4-(hydroxymethyl)phenyl) amino)- 1 -oxo-5-ureidopentan-2-yl)amino)-3-methyl- 1 -oxobutan-2-yl)carbamate Compound E-ll-3 (5g, 13.4 mmol, 1 eq.) was dissolved in a mixture of dry DCM (65 ml) and dry MeOH (35 ml). (4-aminophenyl)methanol (1.81 g, 14.7 mmol, 1.1 eq.) and N-Ethoxycarbonyl-2-ethoxy-l ,2-dihydroquinoline (EEDQ - 6.60 g, 26.7 mmol, 2 eq.) were added and the mixture stirred in the dark overnight. The solvents were evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 5.2 g (73 %) of compound E-ll-4 as an off-white solid. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane;Darkness; | Compound E-ll-3 (5g, 13.4 mmol, 1 eq.) was dissolved in a mixture of dry DCM (65 ml) and dry MeOH (35 ml). (4-aminophenyl)methanol (1.81 g, 14.7 mmol, 1.1 eq.) and N-Ethoxycarbonyl-2-ethoxy-l ,2-dihydroquinoline (EEDQ - 6.60 g, 26.7 mmol, 2 eq.) were added and the mixture stirred in the dark overnight. The solvents were evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 5.2 g (73 %) of compound E-ll-4 as an off-white solid. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane;Darkness; | Compound E-11-4: tert-butyl ((S)-1-(S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate Compound E-11-3 (5 g, 13.4 mmol, 1 eq.) was dissolved in a mixture of dry DCM (65 ml) and dry MeOH (35 ml). (4-aminophenyl)methanol (1.81 g, 14.7 mmol, 1.1 eq.) and N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ -6.60 g, 26.7 mmol, 2 eq.) were added and the mixture stirred in the dark overnight. The solvents were evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 5.2 g (73%) of compound E-11-4 as an off-white solid. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane;Darkness; | Compound E-11-3 (5g, 13.4 mmol, 1 eq.) was dissolved in a mixture of dry DCM (65 ml) and dry MeOH (35 ml). (4-aminophenyl)methanol (1.81 g, 14.7 mmol, 1.1 eq.) and NEthoxycarbonyl-2-ethoxy-i,2-dihydroquinoline (EEDQ - 6.60 g, 26.7 mmol, 2 eq.) were added and the mixture stirred in the dark overnight. The solvents were evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 5.2 g (73 %) ofcompound E-11-4 as an off-white solid. |
71% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 24h; | A solution of Boc-Val-OSu (iO.0 g, 3i.8 mmol, ieq.) in THF (50 mE) was added to a solution of H-Cit-OH (5.85 g, 33.4 mmol, i.05 eq.) and NaHCO3 (2.94 g, 34.9 mmoE, i.i eq.) in THF (50 mE) and H20 (iOO mE). The mixture was stirred at room temperature for 72 hours and the THF was evaporated under reduced pressure. The pH was adjusted to 3 with citric acid to precipitate a white gum. This was extracted with iO% IPAethylacetate (8xi50 mE), the combined extracts were washed with brine (300 mE) and dried (Mg504). Evaporation under reduced pressure gave a white foam which was dried under reduced pressure for i8 hours. The foam was suspended in ether with sonication followed by filtration to give the product as a fine white powder (iO.6 g, 89%).Aportion ofthis material (7.2 g, i9.2 mmol, i eq), p-aminobenzyl alcohol (2.6 g, 2i.i5 mmol, i.i eq.) and EEDQ (9.5 g, 38.5 mmol, 2.0 eq.) in DCM/MeOH (iOO mE/SO mE) were stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residual gum was triturated with ether with sonication, the resulting product was collected by filtration and dried under reduced pressure to give the product 82 as a white solid (6.6 g, 7i%). Analytical Data: RT 2.42 mm; MS (ES) mlz (relative intensity) 479.8 ([M+i], 60), MS (ES-) mlz (relative intensity) 477.6 ([M-H]), 90). |
70% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; | Boc-Val-Cit (1 g. 2.67 mmol, leq) and p-aminobenzyl alcohol (362 mg, 2.94 mmol, 1.1 eq) in 2:1 DCM/MeOH (26 mL/13 mL) were treated with EEDQ (1.32 g, 5.34 mmol, 2 eq). The mixture was stirred in the dark at room temperature overnight The solvents were removed <n="76"/>under vacuum and the resulting solid residue was triturated with 10 mL of ethyl ether. The solid was collected by filtration and washed with ethyl ether to yield the product (900 mg, 70%): 1H NMR (CD3OD) delta 0.93 (3H, d, J = 7.0 Hz), 0.97 (3H, d, J = 7.0 Hz)3 1.44 (9H, s), 1.49-2.06 (5H, m), 3.07-3.29 (2H, m), 3.91 (IH, d, J = 6.7 Hz), 4.50-4.55 (3H, m), 7.29 (2H, d, J = 8.5 Hz), 7.54 (2H, d, J = 8.5 Hz), 8.22 (IH, d, J = 7.3 Hz); 13C NMR (CD3OD) delta 18.64, 19.85, 27.84, 28.75, 30.61, 31.92, 40.28, 54.90, 54.99, 61.73, 64.78, 80.62, 121.09, 128.44, 138.47, 138.55, 158.01, 162.11, 172.00, 174.42, 174.52. |
57.8% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 25℃; for 12h; | To a solution of compound 3.1 (10.0 g, 26.71 mmol, 1 eq) in DCM (40 mL) and MeOH (20 niL) was added EEDQ (13.2 g, 53.41 mmol, 2 eq) and (4-aminophenyl)methanol (3.95 g, 32.05 mmol, 1.2 eq). The mixture was stirred at 25 C for 12 hr. LC-MS showed compound 3.1 was consumed completely and one main peak with desired MS was detected. TLC indicated compound 3.1 was remained, and one major new spot with lower polarity was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 330 g SepaFlash Silica Flash Column, Eluent of 0-15% EtOAc/PE gradient 100 mL/min). Compound 3.2 (7.4 g, 15.43 mmol, 57.8% yield) was obtained as a white solid. MS (ESI) m/z: calcd. for [M+H]+, 480.27; found, 480.1 (M/l+H)+. |
52% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 30℃; for 16h;Darkness; | To a solution of compound 2 (30 g, 80 mmol) in DCM (300 mL) and MeOH (150 mL) was added 4- aminophenyl methanol (1 1 g, 88 mmol) and EEDQ (40 g, 160 mmol) in the dark. The mixture was stirred at 30 C for 16 hr. TLC (DCM:MeOH = 10/1, Rf= 0.43) indicated compound 2 was consumed completely and many new spots formed. The reaction was clean according to TLC. The resulting reaction mixture was concentrated to give a residue, which was purified by flash silica gel chromatography (ISCO; 330 g x 3 SepaFlash Silica Flash Column, Eluent of 0-20% MeOH/Dichloromethane 100 mL/min). Compound 3 (20 g, 52% yield) was obtained as a white solid. |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 18h;Inert atmosphere; | 100074] Boc-Val-Citrulline (ic, 12.93 g, 34.57 mmol) and 4-Aminobenzyl alcohol (PABOH,4.683 g, 38.03 mmol) in CH2C12 (250 mL) and MeOH (125 mL) at room temperature were treated with EEDQ (12.83 g, 51.86 mmol). The reaction mixture was stirred under nitrogen at room temperature for 18 hours. The solvents were removed and the white solid residue was triturated with ether. The solid was collected by filtration , washed with ether and concentrated under reduced pressure to give Boc-Val-Cit-PABOH (id). ?H NMR (500 MHz, DMSO-d6): & 7.54 (d, 2H), 7.29 (d, 1H), 4.52 (s, 2H), 3.90 (d, 1H), 3.19 (m, 1H), 3.10 (m, 1H), 1.51-20.6 (m, 511), 1.44 (s, 911), 0.97 (d, 3H), 0.92 (d, 3H). MS (M+1 ): 480.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 1h; | To a suspension of Boc-Val-Cit-PAB (214 mg, 0.45 mmol, 1 eq) in 3 mL of CH3CN was added DIEA (0.23 mL, 1.35 mmol, 3 eq) followed by dropwise addition of a solution of MsCl (0.1 mL, 1.35 mmol, 3 eq) in 1 mL CH3CN. After 1 hour, TLC showed no starting material left (CHCl3-MeOH, 5:1, v/v). The reaction mixture was evaporated under vacuum and the resulting residue was dissolved in EtOAc. The organic phase was washed with saturated NH4Cl, saturated NaHCO3 and brine; dried over MgSO4, filtered and evaporated under vacuum. To the crude residue dissolved in 5 mL of DMF were added SN38 (88 mg, 0.22 mmol, 0.5 eq) and K2CO3 (31 mg, 0.22 eq, 0.5 eq) and the mixture was heated at 60 C for 3 hours. The product formation was monitored and conformed to product prepared in Example 14 by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyridine; In tetrahydrofuran; dichloromethane; at 20℃; for 3h; | A solution of <strong>[870487-09-5]Boc-Val-Cit-PABOH</strong> (178 mg, 0.370 mmole) in THF (8 mL) in CH2C12 (4 mL) was stirred at room temperature with PNP chloroformate (160 mg, 0.80 minole) and pyridine (65 muL, 0.80 mmole) for 3 h. Ethyl acetate (100 mL) and 10% aqueous citric acid (50 mL) were added to the reaction mixture and organic layer was washed with brine, dried and concentrated and the residue was purified by flash chromatography on silica gel with 5% methanol in as eluent to give the title compound as a white solid (165 mg, 70%). ¹H NMR (CD30D) 8 0.93 (dd, 3H), 0.97 (dd, 3H), 1.44 (s, 9H), 1.58 (m, 2H), 1.75 (m, 1H), 1.89 (m, 1H), 2.05 (m, 1H), 3.10 (m, 1H), 3.20 (m, 1H), 3.90 (d, 1H), 4.51 (m, 1H), 4.55 (s, 2H), 7.29 (d, 2H), 7.55 (d, 2H) ppm; LC-MS (ESI) 545 (M + H+ - Boc), 645 (M + H+), 667 (M + Na+), 683 (M + If). |
69% | With pyridine; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide; for 2h; | <strong>[870487-09-5]Boc-Val-Cit-PAB-OH</strong> 26 (100 mg, 0.2 mmol) was suspended in a mixture of anhydrous DMF (1 mL), THF (2 mL) and CH2Cl2 (1 mL), followed by the addition of pyridine (97 muL, 1.2 mmol) and 4-nitrobenzoyl chloride (115 mg, 0.62 mmol). After 2 hours the solvent was removed and purified by silica gel chromatography eluting with CH2Cl2 (100%), then 5% MeOH/CH2Cl2 to give 89 mg (69%) of Boc-Val-Cit-PAB-OpNP 55. Then, MMAE (88.6 mg, 0.123 mmol) was dissolved in a mixture of THF (2.8 mL) and pyridine (0.7 mL) followed by the addition of DIPEA (212 muL), HOBt (5.6 mg, 0.039 mmol) and Boc-Val-Cit-PAB-OpNP 55 (89 mg, 0.138 mmol). After 48 hours the solvent was removed and the reaction mixture was then purified by silica gel chromatography eluting with CH2Cl2 (100%/o), then 15% MeOH/CH2Cl2 to give 30 mg (45%) of Boc-Val-Cit-PAB-MMAE 56. |
40.92% | With pyridine; In tetrahydrofuran; dichloromethane; at 25℃; for 5h; | To a solution of Compound 3 (4.00 g, 8.34 mmol, 1.00 eq) and 4-nitrophenyl carbonochloridate (6.72 g, 33.36 mmol, 4.00 eq) in THF (20.00 mL) and DCM (10.00 mL) was added PYRIDINE (2.64 g, 33.36 mmol, 2.69 mL, 4.00 eq). And the reaction mixture was stirred at 25 C for 5 hr. LC-MS showed Compound 3 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO; 120 g SepaFlash Silica Flash Column, Eluent of 0-20% DM/MeOH 85 mL/min). Compound 4 (2.20 g, 3.41 mmol, 40.92% yield) was obtained as a white solid. |
40.92% | With pyridine; In tetrahydrofuran; dichloromethane; at 25℃; for 5h; | To a solution of Compound 3 (4.00 g, 8.34 mmol, 1.00 eq) and 4-nitrophenyl carbonochloridate (6.72 g, 33.36 mmol, 4.00 eq) in THF (20.00 mL) and DCM (10.00 mL) was added PYRIDINE (2.64 g, 33.36 mmol, 2.69 mL, 4.00 eq). And the reaction mixture was stirred at 25 C for 5 hr. LC-MSshowed Compound 3 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO; 120 g SepaFlash Silica Flash Column, Eluent of 0--20% DM/MeOH 85 mL/min). Compound 4 (2.20 g, 3.41 mmol, 40.92% yield) was obtained as a white solid. |
With pyridine; In dichloromethane; at 0 - 20℃; for 18h;Inert atmosphere; | 100076] <strong>[870487-09-5]Boc-Val-Cit-PABOH</strong> (id, 9.56 g, 19.95 mmol) under argon at room temperature was dissolved in dry pyridine (3.50 mL). The solution was cooled to 0C, and 4-nitrophenyl chloroformate (8.69 g, 43.13 mmol) in CH2C12 was slowly added into the solution. The reaction mixture was stirred under nitrogen at room temperature for 18 hours. Remove the organic solvent, add 10% citric acid to the solution and then extracted with 10% IPA / EA. The organic layer was washed with brine, dried over MgSO4(s), and concentrated under reduced pressure to give white solid. The purified by column chromatography to give Boc-Val-Cit-PABC-PNP (le). ?H NMR (500 MHz, DMSO-d6): 3: 8.30 (d, 211), 7.64 (d, 211), 7.46 (d, 211), 7.41 (d, 211), 5.25 (s, 2H), 4.52 (s, 1H), 3.90 (d, 1H), 3.20 (m, 1H),3.10 (m, 111), 1.51-20.6 (m, 5H), 1.44 (s, 9H), 0.97 (d, 3H), 0.92 (d, 3H). MS (M+1 ):645.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In tetrahydrofuran; methanol; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | Boc-Val-Cit-PABOH (82) A solution of Boc-Val-OSu (10.0 g, 31.8 mmol, 1 eq.) in THF (50 mL) was added to a solution of H-Cit-OH (5.85 g, 33.4 mmol, 1.05 eq.) and NaHCO3 (2.94 g, 34.9 mmoL, 1.1 eq.) in THF (50 mL) and H2O (100 mL). The mixture was stirred at room temperature for 72 hours and the THF was evaporated under reduced pressure. The pH was adjusted to 3 with citric acid to precipitate a white gum. This was extracted with 10% IPA/ethylacetate (8*150 mL), the combined extracts were washed with brine (300 mL) and dried (MgSO4). Evaporation under reduced pressure gave a white foam which was dried under reduced pressure for 18 hours. The foam was suspended in ether with sonication followed by filtration to give the product as a fine white powder (10.6 g, 89%). A portion of this material (7.2 g, 19.2 mmol, 1 eq), p-aminobenzyl alcohol (2.6 g, 21.15 mmol, 1.1 eq.) and EEDQ (9.5 g, 38.5 mmol, 2.0 eq.) in DCM/MeOH (100 mL/50 mL) were stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residual gum was triturated with ether with sonication, the resulting product was collected by filtration and dried under reduced pressure to give the product 82 as a white solid (6.6 g, 71%). Analytical Data: RT 2.42 min; MS (ES+) m/z (relative intensity) 479.8 ([M+1]+., 60), MS (ES-) m/z (relative intensity) 477.6 ([M-H])-., 90). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In N,N-dimethyl-formamide; at 20℃; for 24h; | Compound 13-6: The mixture of compound 13-4 (435 mg, 1.16 mmol) and ValCit-PABOH 13-51( 400mg, 1.054 mmol) in 12 mL of DMF was stirred at ambient5 temperature for 24 hours. The solvent was removed in vacuo. The residue was treated withether, filtered and washed with ether. The solid was dried in vacuo to give 660mg (98%) ofcompound 13-6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With 4-(Methylamino)pyridine; In N,N-dimethyl-formamide; at 20 - 25℃; for 19h;Inert atmosphere; | Preparation Example 3-18: Preparation of Compound (IV-22) (0285) (0286) A solution of compound (III-22) (1.27 g, 1.63 mmol), obtained in Preparation Example 2-18, in 20 mL of dichloromethane was cooled to -50 to -60C, and added with pyridine (1.3 mL, 16.28 mmol). To the reaction mixture, drops of a solution of p-nitrophenyl chloroformate (16.28 g, 3.3 mmol) in 10 mL of dichloromethane were slowly added over 20 min, followed by stirring at -50 to -60C for 3 hrs. When the reaction was completed, 20 mL of dichloromethane was further added to the reaction mixture, which was then extracted with a 0.5 M potassium hydrogen sulfite solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated in a vacuum. The concentrate was purified by silica gel column chromatography to afford (3S, 5S)-1-((3R, 4S, 5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N, 3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)-5-((1R, 2R)-3-((2-(3-fluoro-4-methoxyphenyl)-2-oxoethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-3-yl (4-nitrophenyl) carbonate (0.8 g, 54%). (0287) LC-MS m/z: 945.7 [M+H]+, 967.7 [M+Na]+ (0288) Under an argon stream, this compound (0.3 g, 0.32 mmol) was dissolved, together with <strong>[870487-09-5]t-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate</strong> (0.3 g, 0.64mmol), in 10 mL of anhydrous dimethyl formamide, and added with 4-methylaminopyridine (0.039 g, 0.32mmol). The reaction mixture was stirred at 20 - 25C for 19 hrs. After completion of the reaction, the reaction mixture was concentrated to the completion in a high vacuum, and the concentrate was purified by silica gel column chromatography to obtain an amino-protected derivative (0.1 g, 25%). (0289) LC-MS m/z: 1285.5 [M+H]+ (0290) To a solution of this amino-protected compound (0.18 g, 0.14 mmol) in 8 mL of dichloromethane was added 2 mL of trifluoroacetic acid, followed by stirring at 20 - 25C for 3 hrs. When the reaction was completed, trifluoroacetic acid was completely removed by adding 5 ml of toluene twice, before a further reaction. (0291) This concentrate (TFA salt) was dissolved, together with 2, 5-dioxopyrrolidin-1-yl 6-(2, 5-dioxo-2, 5-dihydro-1-pyrrol-1-yl)hexanoate, in 10 mL of dimethylformamide, and added with triethylamine (0.1 mL, 0.7 mmol) at room temperature before being stirred at room temperature for 18 hrs. After completion of the reaction, the reaction mixture was concentrated to the completion in a high vacuum, and the concentrate was purified by silica gel column chromatography to obtain the title compound (0.14 g, 71%). (0292) 1H NMR (400 MHz, DMSO-d6) delta 0.70-0.78 (m, 6H), 0.81-0.92 (m, 13H), 1.16-1.24 (23H), 1.46-1.51 (m, 4H), 1.84-1.97 (m, 3H), 3.06-3.17 (m, 12H), 3.30-3.38 (m, 15H), 3.84-3.93 (m, 3H), 4.08-4.85 (m, 8H), 4.86-5.04 (m, 1H), 5.10 (s, 2H), 5.40 (s, 2H), 6.03 (t, 1H), 7.00 (s, 1H), 7.15-7.35 (m, 2H), 7.53-7.55 (d, 1H), 7.77-7.98 (m, 2H), 8.10-8.12 (d, 1H), 8.19-8.48 (m, 1H), 9.44-9.49 (brs, 1H), 10.03 (s, 1H) (0293) LC-MS m/z : 1378.7 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Compound E-1 1-5: tert-butyl ((5)-3-methyl- 1 -(((5)-i -((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)- 1 -oxo-5 -ureidopentan-2-yl)amino)- 1 -oxobutan-2-yl)carbamate Compound E-11-4 (1.1 g, 2.29 mmol, 1 eq.) was dissolved in dry DMF (5 ml) at ambient temperature under an inert atmosphere. Bis(4-nitrophenyl) carbonate (1.40 g, 4.59 mmol, 2 eq.) was added, followed by DIEA (600 tl, 3.44 mmol, 1.5 eq.), and theresulting yellow solution stirred overnight. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 1.27 g (84 %) of compound E-11-5 as an off-white solid. |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Compound E-ll-5: tert-butyl ((S)-3-methyl-l-(((S)-l-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-l-oxo-5-ureidopentan-2-yl)amino)- l- xobutan-2-yl)carbamate Compound E-ll-4 (1.1 g, 2.29 mmol, 1 eq.) was dissolved in dry DMF (5 ml) at ambient temperature under an inert atmosphere. Bis(4-nitrophenyl) carbonate (1.40 g, 4.59 mmol, 2 eq.) was added, followed by DIEA (600 mu, 3.44 mmol, 1.5 eq.), and the resulting yellow solution stirred overnight. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 1.27 g (84 %) of compound E-ll-5 as an off- white solid. |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Compound E-ll-4 (1.1 g, 2.29 mmol, 1 eq.) was dissolved in dry DMF (5 ml) at ambient temperature under an inert atmosphere. Bis(4-nitrophenyl) carbonate (1.40 g, 4.59 mmol, 2 eq.) was added, followed by DIEA (600 mu, 3.44 mmol, 1.5 eq.), and the resulting yellow solution stirred overnight. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 1.27 g (84 %) of compound E-ll-5 as an off- white solid. |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Compound E-11-5: tert-butyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate Compound E-11-4 (1.1 g, 2.29 mmol, 1 eq.) was dissolved in dry DMF (5 ml) at ambient temperature under an inert atmosphere. Bis(4-nitrophenyl) carbonate (1.40 g, 4.59 mmol, 2 eq.) was added, followed by DIEA (600 mul, 3.44 mmol, 1.5 eq.), and the resulting yellow solution stirred overnight. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 1.27 g (84%) of compound E-11-5 as an off-white solid. |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Compound E-11-4 (1.1 g, 2.29 mmol, 1 eq.) was dissolved in dry DMF (5 ml) at ambient temperature under an inert atmosphere. Bis(4-nitrophenyl) carbonate (1.40 g, 4.59 mmol, 2 eq.) was added, followed by DIEA (600 tl, 3.44 mmol, 1.5 eq.), and the resultingyellow solution stirred overnight. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 1.27 g (84 %) of compound E-11-5 as an off-white solid. |
64.47% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 1h; | To a solution of compound 3.2 (3.0 g, 6.26 mmol, 1 eq) in DIVIF (10 mL) was added DIPEA (2.4 g, 18.77 mmol, 3.3 mL, 3 eq) and bis(4-nitrophenyl) carbonate (3.8 g, 12.51 mmol, 2 eq). The mixture was stirred at 25 C for 1 hr. LC-MS showed compound 3.2 was consumed completely and one main peak with desired MS was detected. The reaction was directly purified by prep-HPLC (ACN/H20 condition). Compound 3.3 (2.6 g, 4.03 mmol, 64.47% yield) was obtained as a white solid. MS (ESI) m/z: calcd. for [M+Hf?, 645.28; found, 645.1 (M/1+H)t |
60% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 1h;Inert atmosphere; | To a solution of compound 3 (5.0 g, 10.4 mmol) in DMF (40 mL) was added DIEA (5.4 g, 7.26 mL, 41.7 mmol) and bis(4-nitrophenyl) carbonate (12.7 g, 41.7 mmol). The mixture was stirred at 0 C and under nitrogen for 1 hr. TLC (DCM:MeOH = 10/1, Rf= 0.66) indicated compound 3 was consumed completely and one new spot formed. The reaction was clean according to TLC and LCMS (ES8241-10-P1A, product: RT = 1.15 min) showed the desired product was formed. The resulting reaction mixture was purified directly by prep-HPLC under neutral condition. Compound 4 (12 g, 60% yield) was obtained as a white solid. |
60% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 1h;Inert atmosphere; | To a solution of compound 3 (5.0 g, 10.4 mmol) in DMF (40 mL) was added DIEA (5.4 g, 7.26 mL, 41.7 mmol) and bis(4-nitrophenyl) carbonate (12.7 g, 41.7 mmol). The mixture was stirred at 0 C and under nitrogen for 1 hr. TLC (DCM:MeOH = 10/1, Rf = 0.66) indicated compound 3 wasconsumed completely and one new spot formed. The reaction was clean according to TLC and LCMS (E58241-10-P1A, product: RT = 1.15 mm) showed the desired product was formed. The resulting reaction mixture was purified directly by prep-HPLC under neutral condition. Compound 4 (12 g, 60% yield) was obtained as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | Compound E-12-1: tert-butyl ((S)-3-methyl- 1 -oxo- 1 -(((S)- 1 -oxo- 1 -((4- ((((perfluorophenoxy)carbonyl)oxy)methyl)phenyl)amino)-5 -ureidopentan-2-yl)amino)butan-2-yl)carbamate Compound E-11-4 (670 mg, 1.26 mmol, 1 eq.) was dissolved in dry DMF (6 ml) at 0C under an inert atmosphere. Bis(perfluorophenyl) carbonate (991 mg, 2.51 mmol, 2 eq.) was added, followed by DIEA (329 tl, 1.89 mmol, 1.5 eq.), and the resulting colourless solution stirred for 30 minutes at room temperature. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 836 mg (96 %) of compound E-12-1 as an off-white solid. |
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | Compound E-12-1: tert-butyl ((S)-3-methyl-l-oxo-l-(((S)-l- ((((perfluorophenoxy)carbonyl)oxy)methyl)phenyl)amino)-5-ureidopentan-2- yl)amino)butan-2-yl)carbamate Compound E-ll-4 (670 mg, 1.26 mmol, 1 eq.) was dissolved in dry DMF (6 ml) at 0C under an inert atmosphere. Bis(perfluorophenyl) carbonate (991 mg, 2.51 mmol, 2 eq.) was added, followed by DIEA (329 mu, 1.89 mmol, 1.5 eq.), and the resulting colourless solution stirred for 30 minutes at room temperature. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 836 mg (96 %) of compound E-12-1 as an off-white solid |
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | Compound E-ll-4 (670 mg, 1.26 mmol, 1 eq.) was dissolved in dry DMF (6 ml) at 0C under an inert atmosphere. Bis(perfluorophenyl) carbonate (991 mg, 2.51 mmol, 2 eq.) was added, followed by DIEA (329 mu, 1.89 mmol, 1.5 eq.), and the resulting colourless solution stirred for 30 minutes at room temperature. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 836 mg (96 %) of compound E-12-1 as an off-white solid. |
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | Compound E-11-4 (670 mg, 1.26 mmol, 1 eq.) was dissolved in dry DMF (6 ml) at 0 C. under an inert atmosphere. Bis(perfluorophenyl) carbonate (991 mg, 2.51 mmol, 2 eq.) was added, followed by DIEA (329 mul, 1.89 mmol, 1.5 eq.), and the resulting colourless solution stirred for 30 minutes at room temperature. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 836 mg (96%) of compound E-12-1 as an off-white solid. |
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | Compound E-11-4 (670 mg, 1.26 mmol, 1 eq.) was dissolved in dry DMF (6 ml) at 0C under an inert atmosphere. Bis(perfluorophenyl) carbonate (991 mg, 2.51 mmol, 2 eq.)was added, followed by DIEA (329 tl, 1.89 mmol, 1.5 eq.), and the resulting colourless solution stirred for 30 minutes at room temperature. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 836 mg (96 %) of compound E-12-1 as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 3h; | Example 2.1.4 (31.8 g) was dissolved in dichloromethane (650 mL) and to the solution was added trifluoroacetic acid (4.85 mL). The reaction mixture was stirred for three hours at room temperature. The solvent was concentrated under reduced pressure to yield a mixture of the crude title compound and 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl 2,2,2- trifluoroacetate. The crude material was dissolved in a 1 : 1 dioxane/water solution (300 mL) and to the solution was added sodium hydroxide (5.55 g). The mixture was stirred for three hours at room temperature. The solvent was concentrated under vacuum, and the crude product was purified by reverse phase HPLC using a CombiFlash system, eluting with a gradient of 5-60% acetonitrile in water containing 0.05% v/v ammonium hydroxide, to give the title compound. MS (ESI) m/e 380.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (9.69 g) was dissolved in N,N- dimethylformamide (200 mL). To the solution was added 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)- 1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (18.65 g), and the reaction was stirred for one hour at room temperature. Example 2.1.2 (12.5 g) and N,N-diisopropylethylamine (15.58 mL) were added and the reaction mixture was stirred for 16 hours at room temperature. The solvent was con- concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 10% methanol in dichloromethane, to give the title compound. MS (ESI) m/e 480.2 (M+H)+. | ||
[0001028] (S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (9.69 g) was dissolved in N,N- dimethylformamide (200 mL). To the solution was added 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)- 1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (18.65 g), and the reaction was stirred for one hour at room temperature. Example 2.96.2 (12.5 g) and N,N-diisopropylethylamine (15.58 mL) were added and the reaction mixture was stirred for 16 hours at room temperature. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 10% methanol in dichloromethane, to give the title compound. MS (ESI) m/e 480.2 (M+H)+. | ||
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (9.69 g) was dissolved in N,N- dimethylformamide (200 mL). To the solution was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)- 1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (18.65 g), and the reaction was stirred for one hour at room temperature. Example 2.96.2 (12.5 g) and N,N-diisopropylethylamine (15.58 mL) were added and the reaction mixture was stirred for 16 hours at room temperature. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 10% methanol in dichloromethane, to give the title compound. MS (ESI) m/e 480.2 (M+H)+. |
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (9.69 g) was dissolved in N,N30 dimethylformamide (200 mL). To the solution was added 2-(3H-[1,2,3]triazolo[4,5-bjpyridin-3-yl)-1,1,3 ,3-tetramethylisouronium hexafluorophosphate(V) (18.65 g), and the reaction was stirred for one hour at room temperature. Example 2.1.2 (12.5 g) and N,N-diisopropylethylamine (15.58 mL) were added and the reaction mixture was stirred for 16 hours at room temperature. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography,eluting with 10% methanol in dichloromethanc, to give thc titlc compound. MS (ESI) mle 480.2 (M+H). | ||
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (9.69 g) was dissolved in N,N-dimethylformamide (200 mL). To the solution was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1, 1,3,3-tetramethylisouronium hexafluorophosphate(V) (18.65 g), and the reaction was stirred for one hour at room temperature. Example 2.96.2 (12.5 g) and N,N-diisopropylethylamine (15.58 mL) were added and the reaction mixture was stirred for 16 hours at room temperature. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 10% methanol in dichloromethane, to give the title compound. MS (ESI) m/e 480.2 (M+H)+. | ||
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (9.69 g) was dissolved in N,N-dimethylformamide (200 mL). To the solution was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (18.65 g), and the reaction was stirred for one hour at room temperature. Example 2.1.2 (12.5 g) and N,N-diisopropylethylamine (15.58 mL) were added and the reaction mixture was stirred for 16 hours at room temperature. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 10% methanol in dichloromethane, to give the title compound. MS (ESI) m/e 480.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0001029] Example 2.96.3 (31.8 g) was dissolved in dichloromethane (650 mL) and trifluoroacetic acid (4.85 mL) was added to the solution. The reaction mixture was stirred for three hours at room temperature. The solvent was concentrated under reduced pressure to yield a mixture of the crude title compound and 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl 2,2,2- trifluoroacetate. The crude material was dissolved in a 1 : 1 dioxane/water solution (300 mL) and to the solution was added sodium hydroxide (5.55 g). The mixture was stirred for three hours at room temperature. The solvent was concentrated under vacuum, and the crude product was purified by reverse phase HPLC using a CombiFlash system, eluting with a gradient of 5-60% acetonitrile in water containing 0.05% v/v ammonium hydroxide, to give the title compound. MS (ESI) m/e 380.2 (M+H)+. | ||
Example 2.96.3 (31.8 g) was dissolved in dichloromethane (650 mL) and trifluoroacetic acid (4.85 mL) was added to the solution. The reaction mixture was stirred for three hours at room temperature. The solvent was concentrated under reduced pressure to yield a mixture of the crude title compound and 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl 2,2,2- trifluoroacetate. The crude material was dissolved in a 1:1 dioxane/water solution (300 mL) and to the solution was added sodium hydroxide (5.55 g). The mixture was stirred for three hours at room temperature. The solvent was concentrated under vacuum, and the crude product was purified by reverse phase HPLC using a CombiFlash system, eluting with a gradient of 5-60% acetonitrile in water containing 0.05% v/v ammonium hydroxide, to give the title compound. MS (ESI) m/e 380.2 (M+H)+. | ||
Example 2.96.3 (31.8 g) was dissolved in dichloromethane (650 mL) and trifluoroacetic acid (4.85 mL) was added to the solution. The reaction mixture was stirred for three hours at room temperature. The solvent was concentrated under reduced pressure to yield a mixture of the crude title compound and 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl 2,2,2-trifluoroacetate. The crude material was dissolved in a 1:1 dioxane/water solution (300 mL) and to the solution was added sodium hydroxide (5.55 g). The mixture was stirred for three hours at room temperature. The solvent was concentrated under vacuum, and the crude product was purified by reverse phase HPLC using a CombiFlash system, eluting with a gradient of 5-60% acetonitrile in water containing 0.05% v/v ammonium hydroxide, to give the title compound. MS (ESI) m/e 380.2 (M+H)+. |
Example 2.1.4 (31.8 g) was dissolved in dichloromethane (650 mL) and to the solution was added trifluoroacetic acid (4.85 niL). The reaction mixture was stirred for three hours at room temperature.The solvent was concentrated under reduced pressure to yield a mixture of the crude title compound aud 4-((S)-2-((S)-2-arnino-3-methylbutanarnido)-5 -ureidopentanamido)benzyl 2,2,2-trifluoroacetate. The crude material was dissolved in a 1:1 dioxane/water solution (300 mL) and to the solution was added sodium hydroxide (5.55 g). The mixture was stirred for three hours at room temperature. The solvent was concentrated under vacuum, and the crude product was purified by reverse phase HPLCusing a CombiFlash system, eluting with a gradient of 5-60% acetonitrile in water containing 0.05% v/v ammonium hydroxide, to give the title compound. MS (ESI) rn/c 380.2 (M+H). | ||
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 0.666667h; | Boc-Val-Cit-PAB-OH 26 (100 mg, 0.2 mmol) was suspended in anhydrous 37 CH2Cl2 (1.8 mL), and 38 TFA (0.45 mL) was added. The reaction was stirred at 0 C. for 10 min, then warmed to room temperature for another 30 min. The reaction mixture was evaporated to dryness (azeotropic with toluene for 3 times) to get 39 Val-Cit-PAB-OH 27 without further purification. 1H NMR (400 MHz, CDCl3) delta 7.3-6.99 (m, 5H), 4.47 (m, 1H), 4.44 (s, 1H), 3.86 (s, 3H), 3.05 (m, 2H), 2.11 (m, 1H), 1.7 (m, 1H), 1.58 (m, 1H), 1.5 (m, 2H), 0.95 (q, 6H). | |
Example 2.1.4 (31.8 g) was dissolved in dichloromethane (650 mL) and to the solution was added trifluoroacetic acid (4.85 mL). The reaction mixture was stirred for three hours at room temperature. The solvent was concentrated under reduced pressure to yield a mixture of the crude title compound and 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl 2,2,2-trifluoroacetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 3h; | [0001029] Example 2.96.3 (31.8 g) was dissolved in dichloromethane (650 mL) and trifluoroacetic acid (4.85 mL) was added to the solution. The reaction mixture was stirred for three hours at room temperature. The solvent was concentrated under reduced pressure to yield a mixture of the crude title compound and 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl 2,2,2- trifluoroacetate. The crude material was dissolved in a 1 : 1 dioxane/water solution (300 mL) and to the solution was added sodium hydroxide (5.55 g). The mixture was stirred for three hours at room temperature. The solvent was concentrated under vacuum, and the crude product was purified by reverse phase HPLC using a CombiFlash system, eluting with a gradient of 5-60% acetonitrile in water containing 0.05% v/v ammonium hydroxide, to give the title compound. MS (ESI) m/e 380.2 (M+H)+. | |
In dichloromethane; at 20℃; for 3h; | Example 2.96.3 (31.8 g) was dissolved in dichloromethane (650 mL) and trifluoroacetic acid (4.85 mL) was added to the solution. The reaction mixture was stirred for three hours at room temperature. The solvent was concentrated under reduced pressure to yield a mixture of the crude title compound and 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl 2,2,2-trifluoroacetate. The crude material was dissolved in a 1:1 dioxane/water solution (300 mL) and to the solution was added sodium hydroxide (5.55 g). The mixture was stirred for three hours at room temperature. The solvent was concentrated under vacuum, and the crude product was purified by reverse phase HPLC using a CombiFlash system, eluting with a gradient of 5-60% acetonitrile in water containing 0.05% v/v ammonium hydroxide, to give the title compound. MS (ESI) m/e 380.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.028 g | With dmap; In N,N-dimethyl-formamide; at 25℃; for 120h; | A solution of crude compound 15 (135 mg, approx 0.252 mmol), di-peptide 16 (prepared as described in: WO 2015162293 and WO 2015162293; 0.028 g, 0.036 mmol), and DMAP (0.030 g, 0.246 mmol) in DMF (10 mL) was stirred at 25 C for 5 days. The volatiles were then removed under reduced pressure and the residue purified by preparative HPLC (Column = Gemini-NX CI 8 5um, 11 OA, 50 x 30 mm, temp = 25 C; Eluents: A = 0.1 % ammonium hydroxide in water, B = acetonitrile; 40-80% B over 10 min, flow = 60 mL/min; detection = 254 iiM) to give compound 17 (0.028 g, 14%) as an off-white solid. LCMS (Condition B): RT = 6.22 min, m/z = 787.4 [M+H]+; 1H NMR (400 MHz, DMSO- 6) delta 10.13 (s, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.69-7.59 (m, 3H), 7.54 (d, J = 2.3 Hz, 1H), 7.48-7.30 (m, 7H), 7.28 (d, J = 0.8 Hz, 1H), 7.04 (dd, J = 8.7, 2.3 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 5.95 (t, J = 5.9 Hz, 1H), 5.40 (br s, 2H), 5.36 (s, 2H), 5.09 (s, 2H), 4.50-4.41 (m, 1H), 3.87-3.81 (m, 1H), 3.71 (s, 3H), 3.07-2.88 (m, 2H), 2.01-1.90 (m, 1H), 1.73-1.52 (m, 2H), 1.38 (s, 9H), 0.86 (d, J= 6.8 Hz, 3H), 0.81 (d, J= 6.8 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92 mg | With tributylphosphine; di-isopropyl azodicarboxylate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.5h; | To a stirred solution of compound 58 (328 mg), Boc-Val-Cit-PAB (BroadPharm, 688 mg) and tri-M-butylphosphine (700 mu) in DMF (15 mL) at 0 C was slowly added diisopropyl azodicarboxylate (560 mu,). The mixture was allowed to gradually warm to room temperature and was stirred for 2.5 h. The reaction mixture was then directly purified by reverse phase C-18 column chromatography eluting with buffer A (v/v): water:0.1% acetic acid and buffer B (v/v): (0644) acetonitrile:0.1% acetic acid (100:0 v/v to 0:100 v/v). The desired fractions were combined and lyophilised to give compound 67 as a pale yellow solid (92 mg). LC/MS: (ES+) [M+H]+ (1154, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20 - 40℃; for 2h; | Triethylamine (0.14 g, 0.19 mL 1.4 mmol, 2.2 eq.) was added to a stirred solution of the mono-alloc protected bis-aniline (6) (0.505 g, 0.64 mmol, 1 eq.) and triphosgene (0.068 g, 0.23 mmol, 0.36 eq.) in dry THF (10 mL) under an argon atmosphere at room temperature. The reaction mixture was heated to 40 C., a sample was treated with methanol and analysed by LCMS as the methyl carbamate. A solution of the benzyl alcohol (82) (0.46 g, 0.96 mmol, 1.5 eq.) and triethylamine (0.096 g, 0.13 mL, 0.96 mmol, 1.5 eq.) in dry THF/DMF (20 mL/1 mL) was added drop-wise to the freshly prepared isocyanate. The reaction mixture was monitored by LC-MS and was complete after 2 hours at 40 C. The reaction mixture was evaporated to dryness and the residue partitioned between 10% IPA/DCM and water. The organic portion was separated and washed with water (100 mL), brine (100 mL), dried (MgSO4) and evaporated under reduced pressure to give a brown foam. Purification by flash column chromatography [gradient elution chloroform to 93% chloroform/7% methanol in 1% increments] gave the product as a white solid (0.5 g, 60%). Analytical Data: RT 3.42 min; MS (ES+) m/z (relative intensity) 1298 ([M+H]+., 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.47% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 1h; | To a solution of compound 2 (3.0 g, 6.26 mmol, 1 eq) in DMF (10 rriL) was added DIEA (2.4 g, 18.77 mmol, 3.3 mL, 3 eq) and bis(4-nitrophenyl) carbonate (3.8 g, 12.51 mmol, 2 eq). The mixture was stirred at 25 C for 1 hr. LC-MS showed compound 2 was consumed completely and a peak with desired mass (m/z: 645.1 ([M/l+H]+)) was detected. The reaction was directly purified by prep-HPLC (ACN/H2O condition). Compound 3 (2.6 g, 4.03 mmol, 64.47% yield) was obtained as a white solid. Calculated MW: 645.28; observed m/z: 645.1 ([M/l+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In dichloromethane; at 20℃; for 3h; | Example 2.1.4 (31.8 g) was dissolved in dichloromethane (650 mL) and to the solution was added trifluoroacetic acid (4.85 mL). The reaction mixture was stirred for three hours at room temperature. The solvent was concentrated under reduced pressure to yield a mixture of the crude title compound and 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl 2,2,2-trifluoroacetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With pyridine; dmap; In N,N-dimethyl-formamide; at 20℃; for 16h; | 1.4 mmol) in dry DMF (10 mL) were added Boc-vc-PAB (12a) [WO2008/34124 A2] (0.59 g, 1.2 mmol), DMAP (0.30 g, 2.4 mmol) and pyridine (0.29 g, 3.7 mmol). The mixture was stirred at RT for 16 hours until 3a was totally consumed according to LCMS. The reaction mixture was directly purified by reversed phase flash chromatography (50-80% acetonitrile in water) to give intermediate Boc-4a (0.74 g, yield 38%, ESI m/z: 936 (M + H)+) as a white solid, which was dissolved in DCM (40 mL). To 5 mL of the DCM solution (containing 94 mg Boc-4a) was added TFA (0.5 mL) dropwise at 0 C. After stirred at RT for 1.5 hours until the Boc-4a was consumed, which was monitored by LCMS, the resulting mixture was concentrated in vacuo to give crude title product 4a (83 mg, yield 34% from budesonide) as its TFA salt as colorless oil, which can be used without purification for next step synthesis.20 mg of the crude 4a was purified by prep-HPLC (method B) to give pure 4a (8 mg) as free base for plasma stability test. ESI m/z: 836 (M + H)+.1H NMR (400 MHz, DMSOd6) t 10.17 (s, 1H), 8.12 (br s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 10.2 Hz, 3H), 6.17 (d, J = 10.1 Hz, 1H), 5.97 (t, J = 5.7 Hz, 1H), 5.92 (s, 1H), 5.40 (s, 2H), 5.22-5.01 (m, 4H), 4.89-4.62 (m, 3H), 4.53-4.40 (m, 1H), 4.30 (s, 1H), 3.09-2.87 (m, 3H), 2.36-2.22 (m, 1H), 2.14-1.87 (m, 4H), 1.81 (d, J = 5.6 Hz, 2H), 1.75 (s, 2H), 1.62-1.52 (m, 4H), 1.51-1.41 (m, 2H), 1.40-1.19 (m, 8H), 1.18-0.92 (m, 2H), 0.92-0.82 (m, 9H), 0.78 (d, J = 6.8 Hz, 3H) ppm. |
0.74 g | With pyridine; dmap; In N,N-dimethyl-formamide; at 20℃; for 16h; | 1.4 mmol) in dry DMF (10 mL) were added Boc-vc-PAB (12a) [WO2008/34124 A2] (0.59 g, 1.2 mmol), DMAP (0.30 g, 2.4 mmol) and pyridine (0.29 g, 3.7 mmol). The mixture was stirred at RT for 16 hours until 3a was totally consumed according to LCMS. The reaction mixture was directly purified by reversed phase flash chromatography (50-80% acetonitrile in water) to give intermediate Boc-4a (0.74 g, yield 38%, ESI m/z: 936 (M + H)+) as a white solid, which was dissolved in DCM (40 mL). To 5 mL of the DCM solution (containing 94 mg Boc-4a) was added TFA (0.5 mL) dropwise at 0 oC. After stirred at RT for 1.5 hours until the Boc-4a was consumed, which was monitored by LCMS, the resulting mixture was concentrated in vacuo to give crude title product 4a (83 mg, yield 34% from budesonide) as its TFA salt as colorless oil, which can be used without purification for next step synthesis.20 mg of the crude 4a was purified by prep-HPLC (method B) to give pure 4a (8 mg) as free base for plasma stability test. ESI m/z: 836 (M + H)+.1H NMR (400 MHz, DMSOd6) j 10.17 (s, 1H), 8.12 (br s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 10.2 Hz, 3H), 6.17 (d, J = 10.1 Hz, 1H), 5.97 (t, J = 5.7 Hz, 1H), 5.92 (s, 1H), 5.40 (s, 2H), 5.22-5.01 (m, 4H), 4.89-4.62 (m, 3H), 4.53-4.40 (m, 1H), 4.30 (s, 1H), 3.09-2.87 (m, 3H), 2.36-2.22 (m, 1H), 2.14-1.87 (m, 4H), 1.81 (d, J = 5.6 Hz, 2H), 1.75 (s, 2H), 1.62-1.52 (m, 4H), 1.51-1.41 (m, 2H), 1.40-1.19 (m, 8H), 1.18-0.92 (m, 2H), 0.92-0.82 (m, 9H), 0.78 (d, J = 6.8 Hz, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With thionyl chloride; In diethyl ether; at 0 - 20℃; | Commercially available dipeptide <strong>[870487-09-5]Boc-Val-Cit-PAB-OH</strong> (0.490 g, 1.02 mmol) was dissolved in dry Et20 (20 mL) and was cooled to 0C. SOCI2 (82 pL, 1.12 mmol) was added dropwise to the solution and the mixture was stirred at rt overnight. The reaction was stopped by addition of a saturated solution of NaHC03. The layers were separated and the organic layer was dried over MgSO*, filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography, using DCM/MeOH as eluent to provide 0.260 g (51% yield) of Intermediate 2.1. LC-MS: Rt = 4.76 min, m/z = 499 [M+H]+, m/z = 497 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; at 20℃; for 48h; | The title compound was prepared using a procedure in PCT Int. Appl., 2014145090. tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl) phenyl)amino)-1-oxo-5-ureidopentan-2- yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate R18a, (500 mg, 1.04 mmol) was dissolved in a mixture of CH3CN/H2O/TFA (3:1:1 = v/v/v, 12 mL/4 mL/4 mL). The reaction mixture was stirred at room temperature for 48 h. The progress of the reaction was determined to be complete by LCMS. After concentrating in vacuo, the crude product R18b (0.9 g wet) was used directly for the next step without further purification. found 380.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine; In tetrahydrofuran; at -20℃; | Intermediate 89 (0.36g, 0.75 mmol), Pnp0C(=0)Cl (0.18 g, 0.89 mmol) was suspended in THF (40 mL), and DMAP (20mg), and TEA (0.21mL) were added. The reaction mixture immediately formed a suspension, which was stored in a -20 C freezer over weekend. LCMS indicated product formed with about 50% dimer. Volatiles were removed, and the residue was used directly in next step. MS: 645.0 [M+H+] |
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P322 | |
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P378 | |
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H260 | In contact with water releases flammable gases which may ignite spontaneously |
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H311 | Toxic in contact with skin |
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H319 | Causes serious eye irritation |
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H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
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H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
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H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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