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CAS No. : | 159858-21-6 | MDL No. : | MFCD28139060 |
Formula : | C26H32N4O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | N/A |
M.W : | 496.56 g/mol | Pubchem ID : | - |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
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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 |
---|---|---|
98% | With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 0 - 20℃; for 28h; | a) Fmoc-Val-Cit-OH (31) To a solution of Fmoc-Val-OSu (1.00 g, 2.29 mmol) and NaHCCh (260 mg, 3.09 mmol) in H2O (7.5 ml.) at 0 C was added a solution of /.-citrulline (501 mg, 2.87 mmol) in DME (7.5 ml_). THF (4 ml.) was added, the reaction warmed to rt and stirred for 28 h. Upon completion, the reaction was adjusted to pH 10 with saturated aqueous K2CO3 and washed with EtOAc (2 x 50 ml_). The aqueous layer was acidified to pH 4 with 15% aqueous citric acid and the formed gelatinous mixture was filtered. The wet cake was redissolved in THF/MeOH (50 ml_), TBME (100 ml.) was added and the mixture was stirred at rt for 16 h. The mixture was filtered and the filtrate concentrated in vacuo to yield Fmoc-Val-Cit-OH (1.12 g, 2.25 mmol, 98%) as an off-white solid. |
87% | With sodium hydrogencarbonate; In tetrahydrofuran; water; N,N-dimethyl-formamide; at 20℃; | Citrulline (420 mg, 2.41 mmol) ws combined with solid NaHCC (200 mg, 2.38 mmol) and dissolved in water (6.0 mL). To this mixture ws added a solution of compound 3 (1.0 g, 2.29 mmol) in DMF (6 mL). The mixture was stirred for 5 minutes and THF (5 mL) was added and the reaction mixture was stirred overnight at room temperature. (1042) [0556] A 15% Citric acid solution (1 1.5 mL) wns added to the reaction mixture with stirring and a precipitate formed. The mixture was extracted with a 9: 1 mixture of EtOAc / i-PrOH (3 x 15 mL). the combined organic layers were washed with brine twice, dried over MgS04, filtered and evaporated to dryness to give a residue. The residue was sonicated with ether and iterated. (1043) A white solid formed, which was collected by filtration and dried under vacuum to give 1 0 g for a 87% yield. MS (ESI): mie 496.56 (MH)+, 497, (M + Na)+, 519. |
82% | With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; at 20℃; for 16h;Inert atmosphere; | Fmoc-Val-Cit 1. To a solution of l-citrulline (0.274 g, 1.56 mmol) and NaHC03 (0.131 g, 1 .56 mmol) in water (4 mL) was added a solution of Fmoc-Val-Osu (0.650 g, 1.49 mmol) in DME (4 mL). THF (2 mL) was added to aid solubility, and the reaction mixture was stirred for 16 h at ambient temperature. HC1 (2 M, 8 mL) was added, and the white solid product began to precipitate but remained in the organic layer. The mixture was extracted with isopropanol/EtOAc ( 1 : 9, 2 chi 20 mL), and the combined organic suspension was washed with water (2 chi 20 mL). The resultant suspension was concentrated under reduced pressure, and then treated with Et20 (20 mL). After sonication and trituration with Et20, the crude product was collected by filtration, and the crude product was purified by flash chromatography using a pre-packed 50 g silica column [solvent A: MeOH; solvent B: CH2C12; gradient: 0%A / 100%B (1 CV), 0%A / 100%B? 30%A / 70%B (10 CV), 30%A / 70%B (2 CV); flow rate: 40 mL/min; monitored at 254 and 280 nm] to afford Fmoc-protected dipeptide 1 (0.610 g, 1.22 mmol, 82% yield) as a white solid. [000185] NMR (500 MHz, DMSO-d6) delta 8.18 (1 H, d, J = 7.3 Hz), 7.90 (2H, d, J= 7.5 Hz), 7.75 (2H, t, J= 8.0 Hz), 7.41 (3H, q, J = 8.1 Hz), 7.33 (2H, td, J= 6.6, 3.2 Hz), 5.94 (1H, t, J= 5.5 Hz), 5.38 (2H, bs), 4.33 - 4.26 (1 H, m), 4.26 - 4.19 (2H, m), 4.19 - 4.12 (2H, m), 3.93 (1H, dd, J= 9.0, 7.2 Hz), 2.95 (2H, q, J = 6.6 Hz), 2.04 - 1.92 (1H, m), 1.76 - 1.65 (1 H, m), 1.62 - 1.52 (1H, m), 1.46 - 1.34 (2H, m), 0.89 (3H, d, J= 6.8 Hz), 0.87 (3H, d, J= 6.8 Hz). [000186] 1 C NMR (125 MHz, DMSO-d6) delta 173.9, 171.8, 159.2, 156.5, 144.4, 144.2, 141.2, 128.1 , 127.5, 125.9, 120.6, 66.1 , 60.3, 52.4, 47.1 , 31.0, 28.8, 27.2, 19.7, 18.7. |
82% | With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 20℃; for 6h; | Fmoc-val-NHS (1 eq) was added to DME, and L-citrulline (1.05 eq)NaHCO3 (1.05 eq) is dissolved in water.Add THF to dissolve well and stir for 6 hours at room temperature.After completion of the reaction, the organic layer was separated by separatory funnel using EA (1: 1.25) containing citric acid (15%) aqueous solution and 10% isopropanol,Dry with MgSO4. The resulting solid is vacuum dried for 5 hours, then precipitated with ether and filtered. Yield: yellow solid 82%. |
81.7% | With sodium carbonate; In tetrahydrofuran; at 20℃; for 48h;pH 8 - 9; | The 20 g of compound 31 is dissolved in 200 ml of the solvent in the THF, adding 9.64 g (1.2 eq) L - Citrulline, adding 1 M carbonate to pH 8 - 9, the response [...], stirring at the room temperature reaction 48 h, TLC detection reaction is complete. In ice-bath under stirring, aqueous solution of citric acid for adjusting the pH for the reaction solution 3 - 4, isopropyl alcohol: EA=1:5 (40 ml isopropanol + 200 ml EA) extraction 3 times, the organic phase the merger, anhydrous sodium sulfate drying, filtering turns on lathe does, then adding 200 ml of armor uncle ether stirring, the stirring 2 hours after the filtering, the collection filter cake, and placed in a 45 C and dried in the vacuum drying box 18.6 g white solid product, yield by about 81.7%. |
74% | With sodium carbonate; In water; acetonitrile; at 0 - 35℃; | Fmoc-Val-OSu (1 eq.) was dissolved in Acetonitrile (5 vol.) at 20C. Separately, sodium carbonate (1.1 eq.) was solubilized in Water (5 vol.) at 20C and L-Citrulline (1.1 eq.) was then added to give a homogeneous clear solution. Water (0.5 vol.) was added to the Fmoc-Val-OSu solution and the reaction mixture was heated to 35C before adding the prepared citrulline solution dropwise over 10 min. The reaction mixture was stirred at 35 C for 3-4 hours until reaction was complete before being cooled to 20C. Acetonitrile (20 vol.) was then added over 2-3 hours at 20C. The resulting suspension was stirred for 1-3 hours before being cooled to 0-5C over 1-4 hours and stirred at that temperature for 2-3 hours. Solids were filtered, washed and dried under vacuum before being re-dissolved in a mixture of N,N-dimethylformamide (3.9 vol.), 35.9 g/L aqueous NaCl solution (3.9 vol.), 10% isopropanol in Ethyl acetate (19.5 vol.) at 20C. Glacial acetic acid (1.3 vol.) was then added and the pH of the solution was adjusted to <2 with concentrated hydrochloric acid (0.78 vol.). After stirring at 20C for 30 minutes, phases were separated and the aqueous layer was re extracted with Ethyl acetate (6.5 vol.). Combined organic layers were washed three times with a mixture of 179.5 g/L aqueous NaCl solution (6.5 vol.) and anhydrous N,N- Dimethylformamide (0.72 vol.). The resulting organic mixture was concentrated to a white paste and diluted with Methanol (19.5 vol.). The resulting suspension is stirred at 20C for 10-14 hours before being concentrated again to a white paste. Methyl tert-butyl ether (19.5 vol.) was then added and the resulting suspension was stirred at 40C for 1-2 hours. After cooling to 20C and stirring followed by cooling to 0-5C and stirring, solids were filtered, washed and dried under vacuum. Solids were re-slurried twice in a mixture of Methanol (1.3 vol.) and Methyl tert-butyl ether (19.5 vol.) and dried under vacuum (74% yield). MS: m/e 497 (MH)+, 519 (M+Na)+. |
70% | Fmoc- VaI-NHS (2.5 g, 5.73 mmol, 1 eq) in 15 mL of DME was added to a solution of L- citrulline (1.05 g, 6.01 mmol, 1.05 eq) in 8 mL of THF and NaHCO3 (505 mg, 6.01 mmol, 1.05 eq) in 15 mL of water. The mixture was stirred at room temperature overnight. Aqueous citric acid (75 mL of a 15% solution in water) was added and the mixture was extracted with 10% IP A/EtOAc (2 x 100 mL). The organic layers were washed with water (3 x 100 mL) and the solvent was evaporated under vacuum. The resulting solid was triturated with 100 mL of ethyl ether and filtered to yield the product (1.98 g, 70% yield): 1H NMR (DMSCW0) delta 0.86 (3H, d, J = 6.7 Hz), 0.90 (3H5 d, J = 7.0 Hz), 1.40-1.48 (2H, m), 1.51-1.75 (2H, m), 1.98 (IH, sext, J = 6.8 Hz), 2.95 (2H, q, J = 6.2 Hz), 3.93 (IH, dd, J = 7.3, 8.8 Hz), 4.14-4.29 (4 H, m), 5.40 (2H, brs), 5.96 (IH, t, J = 5.6 Hz), 7.32 (2H, t, J = 7.5 Hz), 7.39-7.44 (3H, m), 7.75 (2H} t, J = 6.3 Hz), 7.89 (2H, d, J = 7.3 Hz), 8.19 (IH, d, J = 7.3 Hz); B C NMR (DMSO-ofc) delta 18.31, 19.25, 26.75, 28.40, 30.59, 46.68, 51.91, 59.81, 64.92, 65.65, 119.98, 125.30, 126.94, 127.52, 140.55, 143.61, 143.76, 155.88, 158.58, 171.12, 173.25. | |
45% | With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 20℃; for 16h; | Compound [10] (1 .7 g, 3.9 mmol) in dimethoxyethane (10 ml_) is added to a solution of L-citrulline [1 1 ] (700 mg, 4 mmol) dissolved in a mixture of tetrahydrofuran and aqueous sodium bicarbonate (344 mg, 4 mmol in 10 mL of water). The reaction is stirred at room temperature for 16 hours. A solution of citric acid 15% in water (50 mL) is added and the mixture extracted with 10% isopropyl alcohol in ethyl acetate (2x75 mL). The solvent is removed by rotatory evaporation. After addition of diethyl ether and irradiation with ultrasounds, the formation of a solid is obtained. Filtration followed by washing with diethyl ether gave [12] as a white solid, 870 mg (45%). MS: m/z 495 [M-H]-.1H NMR (400 MHz, DMSO) delta 8.19 (bm 3H), 7.87 (t, J = 25.1 Hz, 2H), 7.77 (t, J = 6.8 Hz, 2H), 7.49 - 7.23 (m, 4H), 5.99 (s, 1 H), 5.43 (s, 2H), 4.45 - 4.08 (m, 4H), 3.97 (t, J = 7.5 Hz, 1 H), 2.99 (d, J = 5.1 Hz, 2H), 2.02 (d, J = 6.1 Hz, 1 H), 1 .74 (s, 1 H), 1 .61 (d, J = 7.5 Hz, 1 H), 1 .44 (s, 2H), 0.91 (dd, J = 12.5, 6.3 Hz, 6H).13C NMR (101 MHz, DMSO) delta 173.4, 171 .3, 169.8, 167.8, 158.8, 156.0, 143.8, 140.7, 127.6, 127.0, 65.7, 59.8, 51 .9, 46.7, 30.5, 26.6, 19.18 (2C). |
44.3% | With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 0 - 20℃; for 24h; | 1.2) Cit (0.4g, 2.3mmol) and NaHCO3 (0.19g, 2.3mmol) were co-dissolved in 50mL distilled water, cooled to 0 C, and a 25mL DME solution of Fmoc-Val-OSu (1g, 2.29mmol) was gradually dropped Add to a mixed solution of Cit and NaHCO3, add another 20mL of tetrahydrofuran to help dissolve, and stir at room temperature for 24h to obtain a reaction solution.1.3) In the reaction solution obtained in step 1.2), saturated potassium carbonate was added dropwise to adjust the pH to 8-9, and then extracted three times with 20 mL of ethyl acetate. The aqueous layer was collected, and the citric acid solution was added to adjust the pH to 3-4. A gelatinous solid precipitated, filtered, and a white gel-like solid was dissolved in a mixed solution of 25 mL of tetrahydrofuran and 10 mL of methanol, and concentrated in a 250 mL round-bottomed flask to 10 mL by rotary evaporation, and 200 mL of methyl tert-butyl ether was added and stirred at 0 C overnight , Filtered and dried under vacuum to obtain the product Fmoc-Val-Cit (0.5 g, yield 44.3%) as a white solid. |
4.83 g | With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 20℃; for 24h; | Add Cit 4.0g (1.05 eq) and 20 ml of THFAn aqueous solution of sodium hydrogencarbonate (60 ml (NaHCO3 2 g, 1.05 eq)).Another 22.35 mmol of Fmoc-Val-OSu was dissolved in 60 ml of DME.This was added to the reaction solution.The reaction solution was stirred at room temperature for 24 hours.After the reaction was completed, 110 ml of a 15% aqueous citric acid solution was added to the system.It was then extracted twice with EA. And 100 ml of methyl tert-butyl ether was added to the white solid and stirred.filter,The filter cake was dried under reduced pressure at 40 C for 4 h to obtain 4.83 g of product.The yield was 65%. |
With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 20℃; | The reaction product of the previous step (16 g, 36.6 mmol) was dissolved in 90 mL of DME, and L-Cit (6.7 g, 38.5 mmol) was dissolved in NaHCO3 (3.2 g, 38.5 mmol) in 90 mL of water to form a salt. In the system,50 mL of THF was solubilized and the reaction was stirred at room temperature overnight until clear.After the reaction is completed,An equal volume of 15% aqueous citric acid solution with THF was added under ice bath.The white solid of the reaction product is completely precipitated.The Buchner funnel was suction filtered until the filtrate was clarified, and the filter cake was drained.Dry in a vacuum oven. After drying, the white solid is ground.Wash with ether,Filtering,A white solid was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 88% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 48h;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 40C 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 88% |
88% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 48h;Darkness; | Add 60 ml of DCM/MeOH=2/1 mixed solvent to the reaction flask.Add Fmoc-vc 2g (4.2mmol) andPABOH 1.04g (2eq),After stirring the dissolved fraction, EEDQ 2.0 g (2 eq) was added.The reaction system was stirred at room temperature for 2.0 d in the dark.After completion of the reaction, concentration under reduced pressure at 40 C gave a white solid.The white solid was collected and stirred with 100 ml of methyl tert-butyl ether.Filtered, the filter cake was washed with methyl tert-butyl ether.The obtained white solid was dried under reduced pressure at 40 C to give 2.2 g.The yield is about 88%. |
87% | With 1-bromo-2,3,4-tri-O-acetyl-alpha-D-glucuronic acid methyl ester; In methanol; dichloromethane; at 20℃; for 48h;Darkness; | The Fmoc-Val-Cit 4 (1.0 g, 2.01 mmol) and p-aminobenzyl alcohol (492 mg, 4.0 mmol) were dissolved in a 1 : 1 solution of dichloromethane / methanol (30 mL). To this mixture was added N-Ethoxycarbonyl-2-ethoxy- 1 ,2-dihy droquinoline (992 mg, 4.0 mol). The reaction flask was wrapped in foil and the hood lights were turned off, while the reaction wns stirred at room temperature for 48 hours. (1046) [0558] The reaction mixture was evaporated to dryness and the resulting solid was titurated with ether. The suspension was stirred overnight in ether, then filtered to give a yellow solid. The solids were again washed with ether to give 990 mg for a 87% yield. MS (ESI): mie 572.66 (Mi l) , 573, (M + Na)+, 595. |
85% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 36h;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: 0%A / 100%B (1 CV), 0%A / 100%B -? 20%A / 80%B (10 CV), 20%A / 80%B (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, 85% 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) delta 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 36h; | 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 82%. |
80% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In water; ethyl acetate; N,N-dimethyl-formamide; at 0 - 5℃; | Fmoc-Val-Cit (1 eq.), HATH (1.4 eq.) were solubilized in a mixture of anhydrous N,N-Dimethylformamide (9.5 vol.) and Ethyl acetate (5 vol.) at 20C. The reaction mixture was then cooled to 0-5C. Separately, a solution of 4-Aminobenzyl alcohol (1.5 eq.) in Ethyl acetate (2 vol.) and anhydrous N,N-Dimethylformamide (0.5 vol.) was prepared. A solution of N,N-Diisopropylethylamine (1.4 eq.) in Ethyl acetate (2 vol.) was also prepared. Water (1 vol.) was added to the cooled Fmoc-Val-Cit/HATU solution before adding the 4- Aminobenzyl alcohol solution quickly. Immediately thereafter, the DIPEA solution was added over 25-35 minutes. The reaction mixture was stirred at 0-5C for 1-2 hours until reaction was complete. Pre-chilled Methyl tert-butyl ether (20 vol.) was then added over 10 minutes and the resulting mixture was stirred for 1-3 hours. Solids were filtered, washed and dried under vacuum. Solids were re-slurried in Acetonitrile (20 vol.), filtered, washed and dried under vacuum (80% yield). MS: m/e 602 (MH)+, 624 (M+Na)+. |
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 (77%). 1H NMR (400 MHz, DMSO-d6) delta=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, 76% yield): 1H NMR (DMSO- |
65% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 16h;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 (65% yield). MS: m/z 624 [M+Na]+.1H NMR (400 MHz, DMSO) delta 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) delta 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. |
59% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 15h; | b) Fmoc-Val-Cit-PABA (32) A solution of Fmoc-Val-Cit-OH 31 (600 mg, 1.21 mmol), 4-aminobenzyl alcohol (298 mg, 2.42 mmol) and 2-Ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline (598 mg, 2.42 mmol) in CH2CI2/MeOH (12.6 ml_, 2:1 ) was stirred at rt for 15 h. Upon completion, the mixture was diluted with Et20 (30 ml_), sonicaated briefly, filtered and washed with Et20 to yield Fmoc- Val-Cit-PABC (428 mg, 0.710 mmol, 59%) as an off-white solid |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃;Darkness; | The reaction product of reaction step b (7.6 g, 15.3 mmol) and PABOH (3.76 g, 30.6 mmol) were dissolved in a mixture of 140 mL of CH2Cl2 and 70 mL of CH3OH.EEDQ (7.5 g, 30.6 mmol) was added in the dark.Stirring at room temperatureReaction, after the reaction is completed, spin the reaction solution,Wash with ether,Filter by suction. |
Yield | Reaction Conditions | Operation in experiment |
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71% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.75h; | 6 Compound 19. Compound 10 (25 mg, 0.033 mMoles, 2 HBr Salt)) was reacted with compound D of Example 5 (21.5 mg, 0.043 mMoles) in 2.5 mL DMF in the presence of HATU (16.5 mg, 0.0433 mMoles) and TEA (10-15 μL) for 45 minutes. The solvent was evaporated and crude purified by reverse phase HPLC to give 25 mg of Compound 17. (71% yield). MS: 1067.0. Compound 17 (0.0187 mMoles) was deprotected with 5% piperidine in DMF (3 mL) in 45 minutes. The solvent was evaporated and the residue washed with diethyl ether to give 18 (MS: 845.2). To a Solution of 0.00935 mMoles of 18 in 3 mL DMF was added Mal-dPEG4-NHS ester (10 mg, 0.019 mMoles) in DCM 1 mL, followed by TEA (5 μL). After 30 minutes the solvents were evaporated and the crude purified by Reverse Phase HPLC to give 5.2 mg of pure Compound 19 (MS: 1243.2, 1266.8 and 1281.2) |
71% | With triethylamine; HATU In N,N-dimethyl-formamide for 0.75h; | 5 Compound 10 (25mg, 0.033 mMoles, 2HBr Salt)) was reacted with compound D of Example 5 (21.5 mg, 0.043 mMoles) in 2.5 mL DMF in the presence of HATU (16.5 mg, 0.0433 mMoles) and TEA (10-15 μL) for 45 minutes. The solvent was evaporated and crude purified by reverse phase HPLC to give 25 mg of Compound 17. (71 % yield). MS: 1067.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 0℃; for 0.0833333 - 0.333333h; | Example 1 GENERAL PROCEDURE 6: HATU MEDIATED PEPTIDE BOND FORMATION To a stirred solution of the carboxylic acid in a minimal amount of dichioromethane or N,N-dimethylformamide or mixture thereof, at 0°C was added HATU(1.05-1.2 equivalents) and either N,N-diisopropylamine (2-4 equivalents) or 2,4,6-collidine (2-4 equivalents). Stirring was continued for a brief induction period (5-20 minutes) at which time the reaction was charged with a solution of the amine in dichioromethane. The reaction was allowed to warm to room temperature and monitored for progress by HPLC-MS. Upon completion, volatiles were removed under reduced pressure and the residual material waspurified by silica gel chromatography or reverse phase HPLC to furnish amide in adequate purity. CompoundA-6: (9H-fluoren-9-yl)methyl (S)-1-((S)-1-(4-(N-((S,E)-2,5-dimethyl-4-((S)- N,3,3-trimethyl-2-((S)-3-methvl-2-(melhylamino)-3-phenylbutananzido)butanamido)hex-2- enoyl)sufamoyl)benzylamino)-1-oxo-5-ureidopentan-2-ylamino)-3-methyi-1-oxobutan-2- ylcarbamate Synthesized from (S,E)-N-(4-(aminomethyl)phenylsulfonyl)-2,5-dimethyl-4- ((S)-N,3 ,3 -trimethyl-2-((S)-3 -methyl-2-(rnethylamino)-3 -phenylbutanarnido)butanamido)hex-2- enamide and Fmoc-Val-Cit-OH according to General Procedure 6 with minor contamination by D1PEA and AcOH. Material used “as is” in the subsequent step.C60H81N9010S calcd. [M+H] 1120.58; found [M+H] 1120.68. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,6-dimethylpyridine; 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 1.5h; | 7 (0294) To a solution of compound 61 (382 mg, 1.20 mmol) and (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid 62 (CAS Reg. No. 557095-84-8, 596 mg, 1.20 mmol) in DMF (5 mL) at 0° C. were added HATU (593 mg, 1.560 mmol) and 2,6-dimethylpyridine (193 mg, 1.800 mmol). The reaction mixture was stirred at RT for 1.5 h. Cold water (50 mL) was added. The solid formed was collected by filtration, washed with water, and dried under vacuum to give a tan solid that was used for next reaction directly. MS (ESI+) m/z 797.5 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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16.9 mg | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 1.5h; | 8.4 Stock solutions of compound 8A (20.0 mg) in DMF (500 μ) and HATU (40.0 mg) in DMF (400 μ) were prepared. To a stirred solution of compound 1A (14.0 mg) in DMF (700 μ) was added aliquots of compound 8A stock solution (126.9 μ) and HATU stock solution (77.8 μ). The reaction solution was cooled to 0 °C before the addition of DIPEA (4.11 μ). The solution was stirred at 0 °C for 50 min before further aliquots of compound 8A stock solution (126.9 μ), HATU stock solution (77.8 μ and DIPEA (4.11 μ) were added. The solution was stirred for 40 min at 0 °C. The reaction solution was purified by reverse phase C18-column chromatography eluting with buffer A (v/v): water:0.05% trifluoroacetic acid and buffer B (v/v): acetonitrile:0.05% trifluoroacetic acid (100:0 v/v to 0: 100 v/v). The solvent was removed by lyophilisation to give 4-(Fmoc-val-cit-amido)-l,6-heptanediamide bis-AHX-DMl compound 9A (assumed quantitative yield, 16.9 mg) as an off-white solid m/z [M+2H-2(H20)]2+ 1055 (100%). |
Yield | Reaction Conditions | Operation in experiment |
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24.8% | Stage #1: (S)-2-((S)-2-((((9H-fluoren-9-yl)-methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid With 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 1h; Stage #2: tert-butyl (2S)-4-methylene-2-(oxazolidin-2-yl)pyrrolidine-1-carboxylate With N-ethyl-N,N-diisopropylamine at 20℃; | A mixture of EC2405 (42.7 mg, 0.20 mmol), 2-aminoethan-1-ol (12.8 tl, 0.21 mmol) and molecular sieves in toluene (1 ml) was stuffed at room temperature for 1.5 hours to generate the tert-butyl (2S)-4-methylene-2-(oxazolidin-2-yl)pyrrolidine-1-carboxylate in situ. A mixture of Fmoc-Val-Cit-OH (0.11 g, 0.22 mmol) and HATU (0.12 g, 0.30 mmol) in DMF (2 ml) was stirred at room temperature for 1 hour, then DIEA (0.11 ml, 0.61 mmol) was added. The tertbutyl (2S)-4-methylene-2- (oxazolidin-2-yl)pyrrolidine- 1 -carboxylate reaction mixture was transferred into this reaction mixture and stirred at room temperature overnight. The crudeproduct was purified with CombiFlash in 0-20% MeOH/DCM to afford 40 mg of EC2369 in24.8 % yield. LCMS: [M+H] mlz = 733.73. |
Yield | Reaction Conditions | Operation in experiment |
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53% | With sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 25 - 30℃; for 48.0h;Cooling with ice; | Step 2 Synthesis of (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid (90) To a solution of compound 89 (40.14 g, 0.229 mol) and NaHCO3 (19.23 g, 0.229 mol) in water (750 mL) was added the solution of compound 88 (100 g, 0.229 mol) in DME (750 mL) dropwise under ice-bath. During the addition, a white suspension was formed. Additional THF (400 mL) was added to improve the solubility. After addition, the solution was stirred at 25-30 C. for 2 days. To the reaction was added saturated aq. K2CO3 to adjust pH to 8-9, then extracted with EtOAc (500 mL*5). The aqueous layer was adjusted pH to 3-4 with aq. citric acid. A gelatinous material was formed and filtered. The wet cake was dissolved in THF (1.5 L). Methanol was added until the solid was dissolved. The solution was concentrated in vacuum to remove 30% of solvent and then cooled to room temperature. TBME (2 L) was added to the solution and the mixture was stirred at room temperature overnight. The mixture was filtered and the wet cake was dried in vacuum to give compound 90 as a white solid 60 g (53%). |
Yield | Reaction Conditions | Operation in experiment |
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60% | Stage #1: (S)-2-((S)-2-((((9H-fluoren-9-yl)-methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid; C14H21N5O2 With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.166667h; | 3 Preparation of compound 38: To compound 37 (261 mg, 0.52 mmol) in 6 mL of DMF was added HATU (217 mg,0.57 mmol), DIEA (362 giL, 2.08 mmol), and amine 36 (213 mg, 0.52 mmol). The mixturewas stirred for 30 mm, then 400 pL of piperidine was added and stirred for 10 mm. The mixture was evaporated and purified by HPLC to give compound 38 (171 mg, 60%). MS mlz 548.3 (M+H). |
60% | Stage #1: (S)-2-((S)-2-((((9H-fluoren-9-yl)-methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid; C14H21N5O2 With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.166667h; | 1 Synthesis of Compound 3 Compound 2 (261 mg, 0.52 mmol) was dissolved in 6 mE of DMF. Then HATU (217 mg, 0.57 mmol), DIEA (362 tE, 2.08 mmol), and amino compound 1(213 mg, 0.52 mmol) were added. After stirred for 30 mm, then 400 pL piperidine was added and stirred for another 10 mm. The reaction solution was concentrated and directly purified by HPEC to obtain compound 3 (171 mg, 60%). MS mlz 548.3 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
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65% | Stage #1: (S)-2-((S)-2-((((9H-fluoren-9-yl)-methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid; C14H21N5O2 With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Stage #2: With trifluoroacetic acid In dichloromethane for 0.5h; | 8 To compound 37 (130 mg, 0.26 mmol) in 3 mL of DMF was added HATU (110 mg,0.29 mmol), DIEA (175 giL, 1 mmol), and amine 36 (110 mg, 0.27 mmol). The mixture was stirred for 30 mm, then concentrated to dryness. The residue was then treated with TFA/DCM (1/4, v/v, 5 mL) for 30 mm. The mixture was evaporated and purified by HPLC to givecompound 66 (108mg, 65%). MS mlz 670.5 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
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70% | Stage #1: Fmoc-Val-OH With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 16h; Stage #2: Citrulline With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; for 16h; | |
69% | Stage #1: Fmoc-Val-OH With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 16h; Stage #2: Citrulline With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water at 20℃; for 16h; | 3.2.3 Synthesis of [(9h-fluorene-9-yl) methoxy] carbonyl}-l-pentyl-l-alanine (6) General procedure: The Fmoc-protected l-valine (compound 5) (30g, 88.5mmol) was completely dissolved in tetrahydrofuran. N-hydroxysuccinimide (10.2g, 88.5mmol) and Dicyclohexylcarbodiimide (18.3g, 88.5mmol) were added to the reaction solution, and the reaction was stirred at room temperature for 16h. The reaction solution was transferred to 0°C. After stirring for 2h, the solid impurities were removed via filtration. The filtrate was concentrated under a reduced pressure to obtain the glassy solid crude product. The crude product was then dissolved in a mixed solvent of 150mL tetrahydrofuran and 200mL of 1,2-dimethoxyethane. An aqueous sodium bicarbonate solution of l-alanine (8.7g, 97.4mmol) was then added. The reaction was stirred at room temperature for 16h. The reaction solution was poured into 350mL of a 15% citric acid aqueous solution, and the solid and dry were filtered out. Furthermore, the solid was dispersed in ether solvent and ultrasonically filtered. The process was repeated three times. Finally, 21.4g of compound 6 were obtained at a 59% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium hydrogencarbonate; In tetrahydrofuran; 1,2-dimethoxyethane; water; at 20℃; for 24h; | Add in 20ml THFCit4.0g(1.05 eq) and 60 ml aqueous solution of sodium bicarbonate (NaHCO3 2g,1.05eq).Another 22.35mmol Fmoc-Val-OSu dissolved in 60ml DME,Then add it to the reaction solution.Reaction solution in the roomThe reaction was stirred at the temperature for 24 hours.After the reaction is completed,Add 15% citric acid aqueous solution to the system, 110mlThen use EA extractionTake twice,Combine organic layers,Concentrate under reduced pressure to give a white solid.Add 100 ml methyl tert-butyl ether to white solidwash,filter,The filter cake was dried under reduced pressure at 40C for 4 hours to obtain 4.83 g of product.Yield 65%. |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: (S)-2-((S)-2-((((9H-fluoren-9-yl)-methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate at 0℃; Stage #2: tert-butyl (S)-1-((S)-1-(((S,E)-6-(4-aminophenylsulfonamido)-2,5-dimethyl-6-oxohex-4-en-3-yl)(methyl)amino)-3,3-dimethyl-1-oxobutan-2-ylamino)-3-methyl-1-oxo-3-phenylbutan-2-yl(methyl)carbamate In dichloromethane at 0 - 20℃; | 1 General Procedure 3: HA TU Mediated Peptide Bond Formation General procedure: To a stirred solution of the carboxylic acid in a minimal amount of dichloromethane or N,N-dimethylformamide or mixture thereof, at 0° C. was added HATU (1.05-1.2 equivalents) and either N,N-diisopropylamine (2-4 equivalents) or 2,4,6-collidine (2-4 equivalents). Stirring was continued for a brief induction period (5-20 minutes) at which time the reaction was charged with a solution of the amine in dichloromethane. The reaction was allowed to warm to room temperature and monitored for progress by HPLC-MS. Upon completion, volatiles were removed under reduced pressure and the residual material was purified by silica gel chromatography or reverse phase HPLC to furnish amide in adequate purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.4% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 24h; | Taking 18 g compound 32 is added to 500 ml of the reaction bottle, for 200 mLDMF after dissolving, adding 8 g (1.0 eq) 4 - [(N-tert-butoxycarbonyl) aminomethyl] aniline, HATU20g (1.5 eq), DIPEA (18 ml, 3 eq), stirring at room temperature for 24 h, TLC detection raw material after the reaction is complete, adding water 200 ml, dichloromethane 200 ml, stirring 10 min after, separating the organic layer, then washed with water twice, each 50 ml, collecting the organic layer, after drying with anhydrous sodium sulfate, filtering the concentrated, shall be brown oily matter, to the oily adding methyl tert-butyl ether 200 ml, stirring 30 min after, the solid washed, filtered, the filter cake is a tert-butyl ether washing 2 times, each 50 ml, collecting filter cake, 50 °C in the vacuum drying box drying to obtain the brown solid 18.9 g, yield 74.4percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: (S)-2-((S)-2-((((9H-fluoren-9-yl)-methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid; tert-butyl [(1S)-2-(4-aminophenyl)-1-(1,3-thiazol-2-yl)ethyl]carbamate With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Stage #2: With trifluoroacetic acid In dichloromethane for 0.166667h; | 9 Preparation of Compound 35 HATU (110 mg, 0.29 mmol), DIEA (181 uL, 1.04 mmol) and Compound 34 (83 mg, 0.26 mmol) were added to the solution of Compound 2 (131 mg, 0.26 mmol dissolved in 4 mE DMF) in turn. Afier stirred for 30 mm, the solution was evaporated under vacuum. The residue was dissolved in 2 mE of DCM and then 1 mE of TFA was added and stirred for 10 mm. The solution was evaporated under vacuum and purified by HPLC to obtain Compound 35 (118 mg, 67%). MS mlz 698.4 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: (S)-2-((S)-2-((((9H-fluoren-9-yl)-methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid; C14H21N5O2 With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Stage #2: With trifluoroacetic acid In dichloromethane for 0.5h; | 2 Example 2 Synthesis of Compound 11 Compound 2 (130 mg, 0.26 mmol) was dissolved in 3 mE of DMF. Then HATU (110mg, 0.29 mmol), DIEA (175 tE, 1 mmol), and amino compound 1 (110 mg, 0.27 mmol) were added. The reaction solution was stirred for 30 mi and evaporated to dryness in vacuo. The residue was dissolved in TFAdichloromethane (1/4, v/v, 5 mE) and stirred for 30 mm. The reaction solution was evaporated to dryness under reduced pressure and purified by HPEC to obtain compound 8 (108 mg, 65%). MS mlz 670.5 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: (S)-2-((S)-2-((((9H-fluoren-9-yl)-methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: tert-butyl N-[(4bS,8S,8aR)-8-([(1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yl]carbamate In N,N-dimethyl-formamide at 20℃; for 20h; Stage #3: With piperidine In N,N-dimethyl-formamide at 20℃; for 6h; | 11-5.5a Intermediates 102a-b General procedure: To a solution of acid (Fmoc-Val-Ala-OH (101a, 1.2 equiv.) or Fmoc-Val-Cit-OH (101b, 1.2 equiv.) in DMF were added HATU (1.2 equiv.) and DIPEA (2.0-3.0 equiv.) at RT. After the mixture was stirred at RT for 5 min, compound 12b (1.0 equiv.) was added. The resulting mixture was stirred at RT for 4-20 h until the amine was consumed according to LCMS. To the mixture was then added piperidine (excess), and the mixture was stirred at RT for 1-6 h until Fmoc was totally removed, as monitored by LCMS. The reaction mixture was filtered through a membrane and the filtrate was directly purified by prep-HPLC (method B) or reverse phase flash chromatography to give compound 102 (38-72% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In N,N-dimethyl-formamide at 20℃; for 10h; | 6 Example 6: Synthesis of SDM-274 A mixture of Fmoc-Val-Cit (9.6 mg, 0.019 mmol), disuccinimidyl carbonate (5.44 mg, 0.02lmmol) and Et3N (2.68 m, 0.019 mmol) was stirred at room temperature for 10 h. Then Gly-MMAF (15.2 mg, 0.019 mmol) and Et3N (8.0 m, 0.058 mmol) was added and the mixture was stirred at room temperature overnight. The crude product was purified by prep HPLC. Compound 3 was obtained as a white powder after lyophilization (12.8 mg, 52 %). MS (ESI): m/e 1267.5 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran at 25℃; | 6 Compound 3. To a solution of (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)-amino)-3-methylbutanamido)-5-ureidopentanoic acid (Fmoc-Val-Cit, 1.681 g, 3.39 mmol) and compound 2 (1.22 g, 6.77 mmol) in THF (5 mL) was added EEDQ (1.674 g, 6.77 mmol). The reaction mixture was stirred at RT overnight. LCMS (M+H-H2O=659.3) showed product formation. The reaction was directly purified on a COMBIFLASH column using 40 g silical gel and eluting with 0-100% MeOH/DCM to yield compound 3 (53% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.8% | Stage #1: (S)-2-((S)-2-((((9H-fluoren-9-yl)-methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In methanol; dichloromethane at 0℃; for 1h; Stage #2: C42H54N2O7S2 With triethylamine In methanol; dichloromethane | 1.3 3. Synthesis of Fmoc-valine-citrulline-garcinic acid (Fmoc-VC-SS-GA) Fmoc-Val-Cit (0.5 g, 1 mmol) was dissolved in 50 mL of dichloromethane and 10 mL of methanol, cooled to 0 ° C, and EDCI (0.25 g, 1.3 mmol) and HOBT (0.18 g, 1.3 mmol) were added. The resulting mixture was After activation at 0 ° C for 1 h, a dichloromethane solution (30 mL) of GA-SS-NH2 (1.69 g, 7.5 mmol) and triethylamine (267 μL, 2 mmol) were added, and the resulting mixture was stirred overnight. After the reaction was completed, the solution was concentrated under reduced pressure, 100 mL of ice water was added, and stored at 4 ° C. overnight, filtered, washed with water three times, and dried under vacuum. Purification by column chromatography (methanol: dichloromethane 1:11) gave Fmoc-VC-SS-GA in a yield of 67.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With DEA In N,N-dimethyl-formamide at 20℃; for 4h; | 5 Example 5: Synthesis of Compound 5 VC1000 (5 g, 10 mmol) was dissolved in 50 mL of DMF, 10 mL of DEA was added, and the mixture was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete.The reaction solution was added with 200 mL of methyl tert-butyl ether to make slurry, and filtered to obtain compound 5 (2.2 g, yield 80%). |
Tags: 159858-21-6 synthesis path| 159858-21-6 SDS| 159858-21-6 COA| 159858-21-6 purity| 159858-21-6 application| 159858-21-6 NMR| 159858-21-6 COA| 159858-21-6 structure
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