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CAS No. : | 159858-22-7 | MDL No. : | MFCD22417106 |
Formula : | C33H39N5O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DALMAZHDNFCDRP-VMPREFPWSA-N |
M.W : | 601.69 | Pubchem ID : | 59165375 |
Synonyms : |
Fmoc-Val-Cit-PAB
|
Num. heavy atoms : | 44 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 18 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 6.0 |
Molar Refractivity : | 166.11 |
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) : | -7.64 cm/s |
Log Po/w (iLOGP) : | 3.24 |
Log Po/w (XLOGP3) : | 3.28 |
Log Po/w (WLOGP) : | 3.27 |
Log Po/w (MLOGP) : | 1.82 |
Log Po/w (SILICOS-IT) : | 3.5 |
Consensus Log Po/w : | 3.02 |
Lipinski : | 3.0 |
Ghose : | None |
Veber : | 2.0 |
Egan : | 1.0 |
Muegge : | 4.0 |
Bioavailability Score : | 0.17 |
Log S (ESOL) : | -4.75 |
Solubility : | 0.0107 mg/ml ; 0.0000177 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -6.56 |
Solubility : | 0.000164 mg/ml ; 0.000000273 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -8.92 |
Solubility : | 0.000000722 mg/ml ; 0.0000000012 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 5.09 |
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 |
---|---|---|
88% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 48 h; Darkness | DCM/MeOH=2/1 mixed solvent 60 ml was added to the reaction flask, followed by addition of Fmoc-vc2g (4.2 mmol) and1.04 g (2 eq) of PABOH was added. After stirring the dissolved portion, 2.0 g (2 eq) of EEDQ was added. The reaction system is protected from light at room temperatureStir the reaction for 2.0 days. After completion of the reaction, the mixture was concentrated under reduced pressure at 40°C to give a white solid. Collect white solids and add methyl tert-butylEthyl ether (100 ml) was stirred and filtered, and the filter cake was washed with methyl tert-butyl ether. The resulting white solid was dried at 40 °C under reduced pressure to give 2.2 g.About 88percent |
85% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 36 h; Darkness; Inert atmosphere | Fmoc-Val-Cit-PABOH 2. To a solution of Fmoc-protected dipeptide 1 (0.30 g, 0.60 mmol) in CH2Cl2/MeOH (2: 1 , 9 mL) was added P-aminobenzyl alcohol (0.12 g, 0.98 mmol ) and EEDQ (0.24 g, 0.98 mmol), and the reaction mixture was stirred in the dark for 1.5 d. The solvents were evaporated, and the resultant was triturated with Et20 (25 mL). The resulting suspension was sonicated for 20 min and left to stand for 30 min. The crude product was collected by filtration and then purified by flash chromatography using a pre-packed 50 g silica column [solvent A: MeOH; solvent B: CH2C12; gradient: 0percentA / 100percentB (1 CV), 0percentA / 100percentB -→ 20percentA / 80percentB (10 CV), 20percentA / 80percentB (2 CV); flow rate: 40 mL/min; monitored at 254 and 280 nm] to afford Fmoc-protected compound 2 (0.31 g, 0.51 mmol, 85percent yield) as a brown solid. [000188] NMR (500 MHz, DMSO-d6) 6 10.00 (1 H, s), 8.13 (1 H, d, J = 7.7 Hz), 7.92 (2H, d, J = 7.5 Hz), 7.81 - 7.71 (2H, m), 7.57 (2H, d, J= 8.4 Hz), 7.49 - 7.40 (3H, m), 7.35 (2H, t, J= 7.4 Hz), 7.26 (2H, d, J = 8.3 Hz), 5.99 (1 H, t, J = 6.5 Hz), 5.43 (2H, s), 5.12 (1 H, t, J= 5.6 Hz), 4.45 (2H, d, J= 5.4 Hz), 4.32 (1H, d,J= 10.1 Hz), 4.29 - 4.19 (3H, m), 4.00 - 3.88 (1H, m), 3.12 - 2.91 (2H, m), 2.09 - 1.94 (1H, m), 1.80-1.31 (4H, m), 0.90 (3H, d, .7=6.6 Hz), 0.88 (3H, d,J=6.7 Hz). [000189] I3C NMR (125 MHz, DMSO-d6) δ 171.7, 170.9, 159.3, 156.6, 144.4, 144.2, 141.2, 138.0, 137.9, 128.1, 127.6, 127.4, 125.8, 120.6, 119.3, 66.2, 63.1, 60.6, 47.2,30.9,30.0, 27.3, 19.7, 18.8, 15.0. |
82% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol at 20℃; for 36 h; | Fmoc-val-cit (1 eq),Add 2 eq of p-aminobenzyl alcohol (2 eq) to DMC / MeOH (2: 1), add EEDQ (2 eq) and shake for 1.5 days at room temperature.After completion of the reaction, the solvent is dried and precipitated with ether. Repeat after filtering with Ether. Yield: yellow solid 82percent. |
77% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 40℃; | Step 3 Synthesis of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (92) To the suspension of compound 90 (70 g, 0.141 mol) in DCM/MeOH (1 L/500 mL) was added compound 91 (34.7 g, 0.282 mol) followed by EEDQ (69.7 g, 0.282 mol). The mixture was stirred at 40° C. overnight. The reaction mixture was filtered and the wet cake was suspended in EtOAc/TBME (500 mL/200 mL) and stirred for 30 min, then filtered. The solid was washed with EtOAc/TBME to provide compound 92 as off-white solid 65 g (77percent). 1H NMR (400 MHz, DMSO-d6) δ=9.98 (s, 1H), 8.11 (d, 1H), 7.87 (d, 2H), 7.77 (m, 2H), 7.52 (d, 2H), 7.39 (m, 3H), 7.30 (m, 2H), 7.21 (d, 2H), 5.97 (m, 1H), 5.41 (s, 2H), 5.10 (m, 1H), 4.42 (m, 3H), 4.22 (m, 3H), 3.90 (m, 1H), 2.93 (m, 2H), 1.98 (m, 1H), 1.50 (m, 2H), 1.30 (m, 2H), 0.84 (m, 6H). |
76% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; | A solution of compound 28 (1 g, 2.01 mmol, leq) andp-aminobenzyl alcohol (273 mg, 2.21 mmol, 1.1 eq) in a mixture of DCM/MeOH (20 mL/10 mL) was treated with EEDQ (996 mg, 4.03 mmol, 2 eq). The mixture was stirred in the dark at room temperature overnight. The solvents were removed 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 (925 mg, 76percent yield): 1H NMR (DMSO- |
65% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16 h; Darkness | EEDQ (840 mg, 3.4 mmol) is added to a solution containing compound [12] (870 mg, 1 .7 mmol) and p-aminobenzyl alcohol (227 mg, 1 .8 mmol) in dichloro- methane/methanol 2:1 (15 mL). The reaction is left in the dark at room temperature for 16 hours. The solvents are removed, and the resulting solid residue filtrated using diethyl ether to give product [14] as a white solid, 660 mg (65percent yield). MS: m/z 624 [M+Na]+.1H NMR (400 MHz, DMSO) δ 10.00 (bs, 1 H), 8.13 (m, 4H), 7.92 (d, J = 7.3 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.51 - 7.10 (m, 2H), 6.02 (s, 1 H), 5.43 (m, 4H), 5.13 (s, 1 H), 4.47 (s, 3H), 4.31 (m 4H), 3.13 - 2.74 (m, 2H), 2.03 (s, 1 H), 1 .83 - 1 .55 (m, 2H), 1 .43 (s, 2H), 0.90 (d, J = 6.7 Hz, 6H).13C NMR (101 MHz, DMSO) δ 171 .2, 170.4, 158.93, 156.15, 144.6, 143.8, 140.7, 137.5, 127.6, 127.2 (2C) 125.3, 120.1 (2C), 1 18.9, 65.7, 62.6, 60.1 , 53.0, 46.7, 31 .0, 30.5, 26.7, 19.6, 18.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With diethylamine In N,N-dimethyl-formamide for 2 h; | [0438] Fmoc-val-cit-PAB-OH (14.61 g, 24.3 mmol, 1.0 eq.; see, e.g., U.S. Patent No. 6,214,345 to Firestone et al.) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication over for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-P AB-OH, which was used in the next step without further purification. Yield: 8.84 g (96percent). Val-cit-PAB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et at, 1993, Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.). The reaction was complete according to HPLC after 2 h. The reaction mixture was concentrated and the resulting oil was precipitated using ethyl acetate (50 mL). After sonicating for 15 min, ether (400 mL) was added and the mixture was sonicated further until all large particles were broken up. The solution was then filtered and the solid dried to provide an off-white solid intermediate. Yield: 11.63 g (96percent); ES-MS m/z 757.9 [M-H] |
96% | With diethylamine In N,N-dimethyl-formamide for 2 h; | [0454] Fmoc-val-cit-P AB-OH (14.61 g, 24.3 mmol, 1.0 eq., see, e.g., U.S. Patent No. 6,214,345 to Firestone et al.) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-P AB-OH, which was used in the next step without further purification. Yield: 8.84 g (96percent). Val-cit-P AB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et al, 1993, EPO <DP n="138"/>Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.). The reaction was complete according to HPLC after 2 h. The reaction mixture was concentrated and the resulting oil was precipitated using ethyl acetate (50 mL). After sonicating for 15 min, ether (400 niL) was added and the mixture was sonicated further until all large particles were broken up. The solution was then filtered and the solid dried to provide an off-white solid intermediate. Yield: 11.63 g (96percent); ES-MS m/z 757.9 [M-H] |
96% | With diethylamine In N,N-dimethyl-formamide for 2 h; | Example 1 - Preparation of compound AB Fmoc-val-cit-PAB-OH (14.61 g, 24.3 mmol), 1.0 eq., ) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication over for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-PAB-OH, which was used in the next step without further purification. Yield: 8.84 g (96percent). Val-cit-PAB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et al., (1993) Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.). |
93% | With diethylamine In 1-methyl-pyrrolidin-2-one at 20℃; for 16 h; Inert atmosphere | Val-Cit-PABOH 3. To a solution of Fmoc-protected compound 2 (0.31 g, 0.51 mmol) in NMP (5 mL) was added diethylamine (1 mL), and the reaction mixture was stirred for 16 h at ambient temperature. The solvent was then evaporated under reduced pressure, and the resulting oil was triturated with CH2C12, and the mixture was sonicated for 30 min. The solid was collected by filtration and washed with CH2C12 (3 x 10 mL) to afford desired compound 3 (0.19 g, 0.49 mmol, 93percent yield) as a brown solid. [000191] NMR (500 MHz, DMSO-d6) δ 10.03 (1H, s), 8.18 (1H, d, J= 6.2 Hz), 7.52 (2H, d, J= 8.4 Hz), 7.22 (2H, d,J = 8.4 Hz), 5.97 (1H, t, J = 5.8 Hz), 5.39 (2H, s), 5.08 (1H, s), 4.51 - 4.43 (3H, m), 3.13 - 2.95 (2H, m), 2.92 (1H, dd, J= 13.2, 6.3 Hz), 1.93 (2H, dd, J= 11.9, 6.5 Hz), 1.74 - 1.61 (1H, m), 1.61 - 1.49 (1H, m), 1.47-1.29 (2H,m),0.87 (3H, d, ,7=6.8 Hz), 0.78 (3H, d, .7=6.8 Hz). [000192] nC NMR (125 MHz, DMSO-d6) δ 170.9, 159.3, 137.9, 137.9, 127.4, 119.4, 63.0, 59.8, 53.0, 31.6,30.5,27.1, 19.8, 17.5. |
90% | at 20℃; for 24 h; | 490 mg (0.815 mmol) of Fmoc-vc-PABOH was added to 10 ml of NMP, dissolved under stirring, and then diethylamine was added.2ml. The reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was concentrated under reduced pressure at 40° C., and 20 ml of DCM was added to the resulting oil and stirred.The crystals were crystallized and filtered. The filter cake was washed with DCM and the resulting solid was dried under reduced pressure to give 277 mg in 90percent yield. |
90% | With diethylamine In 1-methyl-pyrrolidin-2-one at 20℃; for 24 h; | Fmoc-vc-PABOH 490 mg (0.815 mmol) was added to 10 ml of NMP and stirred to dissolve, and then 2 ml of diethylamine was added.The reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was concentrated under reduced pressure at 40 ° C.Crystallization, filtration, filter cake washed with DCM,The obtained solid was dried under reduced pressure to give 277 mg.The yield was 90percent. |
72% | With piperidine In N,N-dimethyl-formamide at 20℃; | To a solution of compound 29 (622 mg, 1.03 mmol) in 10 mL of anhydrous DMF was added piperidine (2 mL). The mixture was stirred at room temperature overnight and then the solvents were evaporated under vacuum. The residue was triturated with DCM and the resulting solid was filtered and washed with DCM to give the product (283 mg, 72percent yield): 1H NMR (DMSO-^) δ 0.79 (3H, d, J = 6.7 Hz), 0.89 (3H, d, J = 6.7 Hz), 1.38-1.42 (2H, m), 1.52-1.68 (2H, m), 1.94 (IH, sext, J = 6.3 Hz), 2.89-3.01 (2H, m), 3.05 (IH, d, J = 4.7 Hz), 4.46 (2H, s), 5.09 (IH, brs), 5.40 (2H, s), 5.98 (IH, t, J = 5.3 Hz), 7.23 (2H, d, J - 8.2 Hz), 7.54 (2H, d, J = 8.5 Hz), 8.14 (IH, brs), 10.03 (IH, s); 13 C NMR (DMSO- |
60% | With piperidine In N,N-dimethyl-formamide at 20℃; for 3 h; | Piperidine (2.2 mL) is added to a solution of compound [14] (660 mg, 1 .09 mmol) in anhydrous dimethylformamide (5 mL) and the reaction left at room temperature for 3 h. The solvent is removed under vacuum and the residue treated with di- chloromethane in order to obtain a solid that is filtered to give product [15], 240 mg (60percent mg). MS: m/z 380 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.1 1 (s, 1 H), 8.25 (s, 1 H), 7.58 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 6.10 (s, 1 H), 5.46 (s, 2H), 4.48 (m, 3H), 3.23 - 3.09 (m, 2H), 3.1 1 - 2.88 (m, 2H), 1 .99 (dd, J = 12.2, 6.4 Hz, 2H), 1 .99 (dd, J = 12.2, 6.4 Hz, 1 H), 1 .81 - 1 .55 (m, 2H), 1 .55 - 1 .28 (m, 2H), 1 .04 - 0.68 (m, 6H).13C NMR (101 MHz, DMSO) δ 173.3, 170.4, 158.9, 137.5, 126.9 (2C), 125.3, 1 19.9 (2C), 62.6, 59.3, 52.6, 31 .1 , 29.9, 26.6, 19.3, 17.0 (2C). |
597 mg | With piperidine In N,N-dimethyl-formamide at 20℃; for 1 h; | Step 2. To a solution of compound 44-3 (2.14 mmol) in DMF (10 mL) was added compound 44-4 (0.6 mL, 4.5 mmol) and stirred at r.t. for 1 h. The mixture was concentrated and washed with MTBE (30 mL x 3), filtered and the filtrate was concentrated to give 44-5 (597 mg, Yield: 70 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1 h; Inert atmosphere | N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5-carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (1.3 g, 2.16 mmol) (prepared as reported in EP0624377A2) and bis(4-nitrophenyl) carbonate (1.32 g, 4.34 mmol) were dissolved in 6 mL of dry DMF under nitrogen atmosphere, DIPEA (0.75 mL, 4.35 mmol) was added and the resulting solution was stirred an hour at room temperature. Diethylether (120 mL) was added, the resulting precipitate is filtered off, washed with diethylether and dried under vacuum affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (1.47 g, 89percent yield).ESI MS: m/z 767 (MH+)1H NMR (400 MHz, DMSO-de) δ 0.86 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H), 1.30 - 1.52 (m, 2 H), 1.60 (m, 1 H), 1.69 (m, 1 H), 1.99 (m, 1 H), 2.90 - 3.10 (m, 2 H), 3.93 (dd, J = 8.9, 7.0 Hz, 1 H), 4.14 - 4.34 (m, 3 H), 4.42 (m, 1 H), 5.24 (s, 2 H), 5.39 (s, 2 H), 5.97 (t, J = 5.5 Hz, 1 H), 7.32 (m, 2 H), 7.42 (m, 5 H), 7.55 (m, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.74 (t, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.31 (m, 2 H), 10.12 (s, 1 H) |
89% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1 h; Inert atmosphere | N-[(9H-fl uoren-9-ylmethoxy)carbonyl]-L-valyl-N5-carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (1.3 g, 2.16 mmcl) (prepared as reported in EP0624377A2) and bis(4-nitrophenyl) carbonate (1.32 g, 4.34 mmol) were dissolved in 6 ml of dry DMF under nitrogen atmosphere, DIPEA (0.75 ml, 4.35 mmol) was added and the resulting solution was stirred an hour at room temperature. Diethylether (120 ml) was added, the resulting precipitate is filtered off,washed with diethylether and dried under vacuum affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (68) (1.47 g, 89percent yield). MS (ESI): 767 [M+H].1H NMR (400 MHz, DMSO-d6) 0.86 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H), 1.30- 1.52 (m, 2 H), 1.60 (m, 1H), 1.69 (m, 1 H), 1.99 (m, 1 H), 2.90-3.10 (m, 2 H), 3.93 (dd, J = 8.9, 7.0 Hz, 1 H), 4.14-4.34 (m, 3 H), 4.42 (m, 1H), 5.24 (s, 2 H), 5.39 (s, 2 H), 5.97 (t, J = 5.5 Hz, 1 H), 7.32 (m, 2 H), 7.42 (m, 5 H), 755 (m, 2 H), 7.65 (d, J 8.4Hz, 2 H), 7.74 (t, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.31 (m, 2 H), 10.12 (s, I H) |
84% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1.5 h; | (0321) (9H-fluoren-9-yl)methyl((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate 84 (0.5 g, 0.831 mmol) was dissolved in DMF (5 mL) and compound 53a (0.506 g, 1.662 mmol) was added, followed by DIEA (0.23 mL, 1.320 mmol) at RT. The reaction mixture was stirred for 1.5 h at RT. LC/MS showed no starting material was left. The reaction mixture was then treated with 30 mL of Et2O and stirred at RT for 30 min. The precipitate that formed was filtered and washed with additional Et2O. The solid was dried under high vacuum to afford (9H-fluoren-9-yl)methyl((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 85 (0.533 gm, 84percent) as an off yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.37-8.22 (m, 2H), 8.12 (d, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 2H), 7.76-7.50 (m, 5H), 7.44-7.15 (m, 7H), 5.96 (t, J=5.5 Hz, 1H), 5.39 (s, 2H), 5.24 (s, 2H), 4.49-4.39 (m, 1H), 4.34-4.10 (m, 3H), 3.93 (dd, J=8.8, 7.3 Hz, 1H), 3.13-2.82 (m, 2H), 2.05-1.88 (m, 1H), 1.75-1.53 (m, 2H), 1.50-1.28 (m, 2H), 0.87 (dd, J=11.1, 6.7 Hz, 6H); MS (ESI+) m/z 767.3 (M+H)+. |
81% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16 h; | To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(p-nitrophenol) carbonate (7.6 g, 25 mmol) in 100 mL of DMF was added 2.92 mL(16.6 mmol) of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was treated with ether, filtered, washed with ether, 5percent citic acid, water, ether and dried in vacuo to give 5.0 g (81percent) of compound 16-9. |
81% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16 h; | Compound 16-9: To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(pnitrophenol)carbonate (7.6 g, 25 mmol) in 100 mL ofDMF was added 2.92 m1(16.6 mmol)of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours.The solvent was removed in vacuo. The residue was treated with ether, filtered, washed with20 ether, 5percent citic acid, water, ether and dried in vacuo to give 5.0 g (81 percent) of compound 16-9.].4-7. |
81% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16 h; | To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(pnitrophenol)carbonate (7.6 g, 25 mmol) in 100 mL of DMF was added 2.92 mL(16.6 mmol) of15 diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. Thesolvent was removed in vacuo. The residue was treated with ether, filtered, washed with ether, 5percentcitic acid, water, ether and dried in vacuo to give 5.0 g (81 percent) of compound 16-9. |
64% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18 h; Inert atmosphere | To a solution of alcohol 59 (Dubowchik, Firestone et al. 2002) (270 mg, 0.45 mmol) in DMF (4 mL) under Ar is added bis(4-nitrophenyl) carbonate (220 mg, 0.72 mmol), followed by i- Pr2NEt (90 pL, 0.51 mmol) and the reaction is stirred at rt. After 18 h, the mixture is diluted with MeOH (10 mL) then concentrated under reduced pressure and the residue is azeotroped with toluene (4 x 10 mL). The crude product is purified by column chromatography on silica gel (MeOH/CHCI3= 0:1 to 1 :4), to afford the title compound 60 as a yellow solid (219 mg, 64percent). H NMR (500 MHz, 3:1 CDCI3/CD3OD) δ 0.95 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.50-1.60 (m, 2H), 1.68-1.75 (m, 1 H), 1.89-1.96 (m, 1H), 2.06- 2.13 (m, 1 H), 3.08-3.13, (m, 1 H), 3.21-3.26, (m, 1 H), 4.00 (d, J = 6.5 Hz, 1 H), 4.22 (dd, J = 6.5, 6.5 Hz, 1 H), 4.35-4.38 (m, 1 H), 4.45-4.49 (m, 1 H), 4.56-4.58 (m, 1 H), 5.25 (s, 2H), 7.31 (dd, J = 7.5, 7.5 Hz, 2H), 7.38-7.41 (m, 6H), 7.61-7.64 (m, 4H), 7.77 (d, J = 7.7 Hz, 2H);3C NMR (126 MHz, 3:1 CDCI3/CD3OD) δ 18.1 , 19.3, 26.6, 29.5, 31.2, 39.2, 53.5, 61.0, 67.3, 70.9, 120.2, 120.4, 122.1 , 125.2, 125.3, 125.5, 127.3, 128.0, 129.8, 139.0, 141.6, 144.0, 144.1 , 145.7, 152.8, 155.9, 157.4, 160.8, 170.9, 172.9; HRMS-ESI: m/z calcd for C oH42N6Oio a [M+Na]+789.2860, found 789.2853. |
57% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; | Step 4 Synthesis of (9H-fluoren-9-yl)methyl ((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 (94) To a solution of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (3.74 g, 8.31 mmol, 92) in anhydrous DMF (120 mL) was added bis(4-nitrophenyl) carbonate (3.78 g, 12.4 mmol, 93) in portions, followed by DIPEA (1.21 g, 9.32 mmol) at 0° C. dropwise. The reaction mixture was stirred at room temperature overnight. TLC (MeOH: CH2Cl2=1:10) showed that the reaction was completed. The reaction mixture was added dropwise to MTBE (2.5 L) with stirring. The crude product was collected by filtration. The filtrate cake was washed with MTBE and dried under high vacuum to afford compound 94 as brown solid 2.7 g (57percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With pyridine In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; | Dissolve Fmoc-val-cit-pab-OH (1 eq) in THF: DMF (5: 1) and slowly add pyridine (4eq) at 0 ° C.4-nitrophenyl carbonochloridate (3 eq) is added and stirred at 0 ° C.The reaction is confirmed by HPLC. After completion of the reaction, the solvent is dried and then columed. Yield: yellow solid 49percent. |