Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 1394238-91-5 | MDL No. : | MFCD28557282 |
Formula : | C30H33N3O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PIEQFKSWCKVBTP-PPHZAIPVSA-N |
M.W : | 515.60 | Pubchem ID : | 100029287 |
Synonyms : |
Fmoc-Val-Ala-PAB
|
Num. heavy atoms : | 38 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.3 |
Num. rotatable bonds : | 13 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 4.0 |
Molar Refractivity : | 145.59 |
TPSA : | 116.76 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.47 cm/s |
Log Po/w (iLOGP) : | 4.14 |
Log Po/w (XLOGP3) : | 4.19 |
Log Po/w (WLOGP) : | 3.84 |
Log Po/w (MLOGP) : | 2.42 |
Log Po/w (SILICOS-IT) : | 4.29 |
Consensus Log Po/w : | 3.78 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.17 |
Solubility : | 0.00349 mg/ml ; 0.00000678 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -6.35 |
Solubility : | 0.00023 mg/ml ; 0.000000446 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -8.56 |
Solubility : | 0.00000142 mg/ml ; 0.0000000028 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 4.77 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-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 |
---|---|---|
100% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 26h; | Compound 21: (9H-fluoren-9-yl)methyl ((S)-1 -(((S)-1 -((4-(hydroxymethyl)phenyl)-amino)-1 -oxopropan-2-yl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate To a solution of Fmoc-Val-Ala-OH (CAS number [150114-97-9], 1 g, 2.44 mmol) in DCM (30 mL) and MeOH (15 mL) were added 4-aminobenzyl alcohol (612 mg, 4.87 mmol) and EEDQ (1 .22 g, 4.87 mmol). The reaction medium was stirred at RT for 24 h then additional 4-aminobenzyl alcohol (612 mg, 4.87 mmol) and EEDQ (1 .22 g, 4.87 mmol) were added and the stirring carried on 2 h. The reaction medium was then concentrated in vacuo; Et20 was added to the crude product, the mixture wasstirred and filtered to give a brown solid that was diluted in Et20 and the mixture was stirred at RT overnight. It was then filtered and the precipitate was dried to give 1 .3 g of compound 21 as a brown solid (quant.).RMN 1H (400 MHz, ö in ppm, DMSO-d6): 0.86 (d, J = 7.0 Hz, 3 H); 0.89 (d, J =7.0 Hz, 3 H); 1.30 (d, J = 7.0 Hz, 3 H); 2.00 (m, 1 H); 3.91 (m, 1 H); 4.19 to 4.34 (m,4 H); 4.43 (d, J = 5.7 Hz, 2 H); 5.08 (t, J = 5.7 Hz, 1 H); 7.23 (d, J = 7.9 Hz, 2 H); 7.31(t, J = 7.9 Hz, 2 H); 7.40 (m, 3 H); 7.53 (d, J = 9.1 Hz, 2 H); 7.73 (t, J = 8.6 Hz, 2 H);7.89 (d, J = 7.9 Hz, 2 H); 8.16 (d, J = 7.3 Hz, 1 H); 9.91 (5, 1 H). LCMS (A): ES m/z =292; m/z = 393; m/z = 516 [Mi-H] tR = 1.21 mm. |
95% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; | |
78% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 72h; Darkness; |
78% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16h; Inert atmosphere; | 4.1.2 (9H-fluoren-9-yl)methyl((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl]amino)-3-methyl-1-oxobutan-2-yl)carbamate (1, Fig. S3) Fmoc-VA4.00g, 9.74mmolwas dissolved in a mixture of DCM and MeOH (120mL), then PAB1.80g, 14.62mmoland EEDQ4.82g, 19.49mmolwas added under N2 atmosphere. The reaction was kept stirring at room temperature for 16h. The product precipitates from solution were filtered off to yield the crude product. Add an appropriate amount of anhydrous ether to the crude product and purification was performed by ultrasound and filtration 3 times to obtain the pure product as a white powder (3.90g, yield: 78%) without need for further purification. 1H NMR (400MHz, DMSO-d6) δ: 0.88 (dd, 6H), 1.30 (d, 3H), 2.00 (m, 1H), 3.91 (t, 1H), 4.22 (q, 2H), 4.30 (t, 1H), 4.40 (br, 1H), 4.42 (d, 2H), 5.13 (t, 1H), 7.24 (t, 2H), 7.34 (t, 2H), 7.41 (t, 2H), 7.52 (q, 3H), 7.75 (t, 2H), 7.89 (d, 2H), 8.22 (d, 1H), 9.96 (s, 1H). MS (ESI) m/z: 516.24 [M+H]+; 538.22 [M+Na]+. |
78% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16h; Inert atmosphere; | 4.1.2 (9H-fluoren-9-yl)methyl((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl]amino)-3-methyl-1-oxobutan-2-yl)carbamate (1, Fig. S3) Fmoc-VA4.00g, 9.74mmolwas dissolved in a mixture of DCM and MeOH (120mL), then PAB1.80g, 14.62mmoland EEDQ4.82g, 19.49mmolwas added under N2 atmosphere. The reaction was kept stirring at room temperature for 16h. The product precipitates from solution were filtered off to yield the crude product. Add an appropriate amount of anhydrous ether to the crude product and purification was performed by ultrasound and filtration 3 times to obtain the pure product as a white powder (3.90g, yield: 78%) without need for further purification. 1H NMR (400MHz, DMSO-d6) δ: 0.88 (dd, 6H), 1.30 (d, 3H), 2.00 (m, 1H), 3.91 (t, 1H), 4.22 (q, 2H), 4.30 (t, 1H), 4.40 (br, 1H), 4.42 (d, 2H), 5.13 (t, 1H), 7.24 (t, 2H), 7.34 (t, 2H), 7.41 (t, 2H), 7.52 (q, 3H), 7.75 (t, 2H), 7.89 (d, 2H), 8.22 (d, 1H), 9.96 (s, 1H). MS (ESI) m/z: 516.24 [M+H]+; 538.22 [M+Na]+. |
77% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 36h; | |
77% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 12h; Darkness; | 4.2 2) Preparation of Fmoc-Val-Ala-PAB 2) Preparation of Fmoc-Val-Ala-PAB Fmoc-Val-Ala (2 g, 4.87 mM) and 4-aminobenzyl alcohol (1.2 g, 9.75 mM) were dissolved in a dichloromethane/methanol mixed solvent (100 mL, the volume ratio of dichloromethane/methanol was 2:1), then 2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 2.41 g, 9.75 mM) was added, and the resulting mixed solution was placed in the dark at room temperature and stirred for 12 hours. The solvent was distilled off under reduced pressure to obtain a white solid residue, which was added to diethyl ether (300 mL), the resultant suspension was treated with ultrasonic for 5 minutes, then stood for 30 minutes, and then was filtered, the filter cake was washed with diethyl ether to obtain a white solid (1.92 g, 77% yield). 1H-NMR (400 MHz, DMSO-d6) δ 9.96(s, 1H), 8.22(d, J=6.7 Hz, 1H), 7.89(d, J=7.6 Hz, 2H), 7.75(t, 2H), 7.52(q, 3H), 7.41(t, 2H), 7.34(t, 2H), 7.24(t, 2H), 5.13(t, J=5.6 Hz, 1H), 4.42(d, J=5.6 Hz, 2H), 4.40(br, 1H), 4.30(t, 1H), 4.22(q, 2H), 3.91(t, J=8.4 Hz, 1H), 2.00(m, 1H), 1.30(d, J=7.0 Hz, 3H), 0.88(dd, 6H). MS(ESI)m/z: 516.4 [M+H]+; 538.3 [M+Na]+. |
77% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 12h; Darkness; | 4.2 2) Preparation of Fmoc-Val-Ala-PAB 2) Preparation of Fmoc-Val-Ala-PAB Fmoc-Val-Ala (2 g, 4.87 mM) and 4-aminobenzyl alcohol (1.2 g, 9.75 mM) were dissolved in a dichloromethane/methanol mixed solvent (100 mL, the volume ratio of dichloromethane/methanol was 2:1), then 2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 2.41 g, 9.75 mM) was added, and the resulting mixed solution was placed in the dark at room temperature and stirred for 12 hours. The solvent was distilled off under reduced pressure to obtain a white solid residue, which was added to diethyl ether (300 mL), the resultant suspension was treated with ultrasonic for 5 minutes, then stood for 30 minutes, and then was filtered, the filter cake was washed with diethyl ether to obtain a white solid (1.92 g, 77% yield). 1H-NMR (400 MHz, DMSO-d6) δ 9.96(s, 1H), 8.22(d, J=6.7 Hz, 1H), 7.89(d, J=7.6 Hz, 2H), 7.75(t, 2H), 7.52(q, 3H), 7.41(t, 2H), 7.34(t, 2H), 7.24(t, 2H), 5.13(t, J=5.6 Hz, 1H), 4.42(d, J=5.6 Hz, 2H), 4.40(br, 1H), 4.30(t, 1H), 4.22(q, 2H), 3.91(t, J=8.4 Hz, 1H), 2.00(m, 1H), 1.30(d, J=7.0 Hz, 3H), 0.88(dd, 6H). MS(ESI)m/z: 516.4 [M+H]+; 538.3 [M+Na]+. |
73% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 36h; Darkness; | 3.2.5 Synthesis of (9h-fluorene-9-yl) methyl [(s)-1-[(s)-1-[4-(hydroxymethyl) phenyl] amino} - 1-oxopropan-2-yl] amino}- 3-1-oxobutane-2-yl] carbamate (8) Compound 6 (5g, 12.2mmol) was dissolved in 200mL of a mixed solution of dichloromethane and methanol, and then p-aminobenzyl alcohol (3g, 24.4mmol) and EEDQ (6g, 24.4mmol) were successively added to the solution. The reaction solution was stirred at room temperature in the dark and reacted overnight. At the end of the reaction, the reaction solution was concentrated under a reduced pressure, and the crude product was dispersed into ether. After stirring for 30min, 4.6g of white powdered solid compound 8 were obtained via filtration, at a yield of 73%. The product was directly used in the next step. |
68% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol Inert atmosphere; | 29 Example 29: Preparation of Compound 48. To a solution of Val-Ala-OH (1 g, 5.31 mM) in water (40 ml) was added Na2CO3 (1.42 g, 13.28 mM) and cooled to 0°C before dioxane (40 mL) was added. A solution of Fmoc-Cl (1.44 g, 5.58 mM) in dioxane (40 mL) was added dropwise over 10 mm at 0°C. The reaction mixture was stirred at 0°C for 2h. Then the reaction mixture was allowed to stir at RT for 16 h.Dioxane was removed under vacuum, the reaction mixture diluted with water (450 mL), pH was adjusted to 2 using iN HC1 and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine, dried over Mg504, filtered, concentrated under reduced pressure and dried to yield Fmoc-Val-Ala-OH. This product was suspended in dry DCM (25 ml), PABA (0.785 g, 6.38 mM) and EEDQ (1.97 1 g, 7.97mM) were added. The resulting mixture was treated under Argon with methanol until a clear solution was obtained. The reaction was stirred overnight and filtered. The filtrate was washed with diethyl ether (4x) and dried under high vacum to yield Compound 48 (1.85 g, 68%). ‘H NMR (500 MHz, CD3OD): (57.79 (d, J,= 8.0 Hz, 2H), 7.65 (t, J,= 7.0 Hz, J2= 7.5 Hz, 2H), 7.54 (d, J,= 8.0 Hz, 2H), 7.38 (t, J,= 7.5 Hz, J2=7.5 Hz, 2H), 7.33-7.24 (m, 4H), 4.54 (s, 2H), 4.48 (q, J,= 14.0 Hz, J2= 7.0 Hz, 1H), 4.42-4.32(m, 2H), 4.22 (t, J,= 7.0 Hz, J2= 6.5 Hz, 1H), 3.94 (d, J,= 7.0 Hz, 1H), 2.07 (m, 1H), 1.43 (d,J,= 7.5 Hz, 3H), 0.97 (d, J,= 7.0 Hz, 3H), 0.95 (d, J,= 7.0 Hz, 3H); LCMS (ESI): (M + H) =Calculated for C30H33N305, 516.24; found 516.24. |
68% | With N-ethoxy-carbonyl-2-ethoxy-1,3-dihydroquinoline In methanol; dichloromethane Inert atmosphere; | 7 Example 7: Synthesis of FA-PBD inhibitor (compound 25) To a solution ofVal-Ala-OH (1 g, 5.31 mM) in water (40 ml) was addedNa2C03 (1.42 g, 13.28 mM) and cooled to 0°C before dioxane (40 mL) was added. A solutionofFmoc-Cl (1.44 g, 5.58 mM) in dioxane (40 mL) was added dropwise over 10 min at 0°C. Thereaction mixture was stirred at 0°C for 2h, then allowed to stir at R T for 16 h. Dioxane was20 removed under vacuum, the reaction mixture diluted with water (450 mL), pH was adjusted to 2using 1N HCl and extracted with EtOAc (3 x 250 mL). The combined organic layers arewashed with brine, dried over MgS04, filtered, concentrated under reduced pressure and driedto yield Fmoc-Val-Ala-OH. This product was suspended in dry DCM (25 ml), PABA (0.785 g,6.38 mM) and EEDQ (1.971 g, 7.97mM) are added. The resulting mixture was treated under25 Argon with methanol until a clear solution was obtained. The reaction was stirred overnight andfiltered. The filtrate was washed with diethyl ether ( 4x) and dried under high vacum to yieldCompound 18 (1.85 g, 68%). 1H NMR (500 MHz, CD30D): J 7.79 (d, h= 8.0 Hz, 2H), 7.65 (t,h= 7.0 Hz, h= 7.5 Hz, 2H), 7.54 (d, h= 8.0 Hz, 2H), 7.38 (t, h= 7.5 Hz, h= 7.5 Hz, 2H), 7.33-7.24 (m, 4H), 4.54 (s, 2H), 4.48 (q, lF 14.0 Hz, h= 7.0 Hz, 1H), 4.42-4.32 (m, 2H), 4.22 (t,lF 7.0 Hz, h= 6.5 Hz, 1H), 3.94 (d, lF 7.0 Hz, 1H), 2.07 (m, 1H), 1.43 (d, lF 7.5 Hz, 3H),0.97 (d, h= 7.0 Hz, 3H), 0.95 (d, h= 7.0 Hz, 3H); LCMS (ESI): (M + Ht =Calculated forC3oH33N30s, 516.24; found 516.24- |
67% | Stage #1: (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)propanoic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In ethyl acetate at 0℃; for 0.5h; Stage #2: 4-aminobenzenemethanol With N-ethyl-N,N-diisopropylamine In ethyl acetate at 0 - 20℃; for 2h; | |
64% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane for 48h; Inert atmosphere; | |
64% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 48h; Inert atmosphere; | 3.b Under an inert gas atmosphere a suspension of 0.36 g Fmoc-Val-Ala-OH 17 (0.88 mmol, 1 eq), 0.13 g 4-aminobenzyl alcohol (1.06 mmol, 1.2 eq) and 0.33 g EEDQ (1.33 mmol, 1.5 eq) in dichloromethane was treated with methanol until a clear solution resulted. During the next two days a precipitate was formed. After filtration, the precipitate was washed with diethyl ether and sonicated for 15 min at room temperature. This procedure was repeated twice and the product 18 was dried in high vacuo (0.29 g, 64%). 1H NMR (DMSO-d6): δ[ppm] 0.86 (d, 3H, J=6.8 Hz), 0.90 (d, 3H, J=6.8 Hz), 1.31 (d, 3H, J=7.1 Hz), 1.96-2.04 (m, 1H), 3.92 (t, 1H, J=7.2 Hz), 4.21-4.34 (m, 3H), 4.40-4.46 (m, 3H), 5.11 (t, 1H, J=5.7 Hz), 7.24 (d, 2H, J=8.5 Hz), 7.33 (t, 2H, J=7.4 Hz), 7.40-7.47 (m, 3H), 7.54 (d, 2H, J=8.4 Hz), 7.75 (t, 2H, J=7.1 Hz), 7.89 (d, 2H, J=7.5 Hz), 8.17 (d, 1H, J=7.0 Hz), 9.93 (bs, 1H). 13C NMR (DMSO-d6): δ[ppm] 18.6, 18.7, 19.6, 30.8, 47.1, 49.4, 60.4, 63.0, 66.1, 119.3, 120.5, 125.8, 127.3, 127.5, 128.0, 128.1, 137.8, 138.0, 141.1, 144.2, 144.3, 156.6, 171.3, 171.4. |
62% | 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 5h; | 1.2 Intermediate 2.4: Fmoc-Val-Ala-PAB-OH Intermediate 2.3 (1.65 g, 4.02 mmol) was dissolved in dry DMF (10 mL). PAB-OH (0.49 g, 4.02 mmol), HATU (1.53 g, 4.02 mmol) and DIEA (2.11 mL, 12.06 mmol) were added to the solution and the mixture was stirred for 5 h. The reaction was stopped by addition of EtOAc and the mixture was washed with saturated NaHC03, water and brine. The layers were separated and the organic layer was dried over MgS04, filtered and concentrated in vacuo. The residue was purified by silica-gel column chromatography, using DCM/Acetone and DCM/MeOH as eluent to provide 1.3 g (62% yield) of Intermediate 2.4. LC-MS: Rt = 5.30 min, m/z = 516 [M+H]+, m/z = 514 [M-H]-. |
60.9% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane Inert atmosphere; | |
59% | With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In tetrahydrofuran at 20℃; for 14h; | Fmoc-VA-PABOH (2b) Compound 1b (1.87 g, 0.0045 mmol) and PABOH1.12 g, 0.009 mmolwere dissolved in THF (40 mL), and HATU2.05 g, 0.0054 mmoland DIEA 1.5 mL were added. The reaction was stirred at room temperature for 14h. After the completion of the reaction, the solvent was removed under reduced pressure to give a crude material, which purified by column chromatography to obtain compound 2a as a light yellow solid powder solid (1.3 g, 59% yield). C30H33N3O5MS (ESI) m/z: 516 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ (ppm): 9.92 (s, 1H), 8.17 (d, J = 7.1 Hz, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.75 (dd, J = 10.6 Hz, 7.5 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.47-7.39 (m, 3H), 7.33 (m, 2H), 7.24 (d, J = 8.2 Hz, 2H), 5.10 (s, 1H), 4.43 (s, 3H), 4.33-4.28 (m, 1H), 4.26-4.20 (m, 2H), 3.92 (dd, J = 8.9 Hz, 7.1 Hz, 1H), 2.01-1.98 (m, 1H), 1.31 (d, J = 7.1 Hz, 3H), 0.88 (m, 6H). |
With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In tetrahydrofuran | ||
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane Inert atmosphere; | ||
1.85 g | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane Inert atmosphere; | 1 To a solution of Val-Ala-OH (1 g, 5.31 mM) in water (40 ml) is added Na2C03(1.42 g, 13.28 mM) and cooled to 0°C before dioxane (40 mL) is added. A solution of Fmoc-Cl (1.44 g, 5.58 mM) in dioxane (40 mL) is added dropwise over 10 min at 0°C. The reaction mixture is stirred at 0°C for 2h, then allowed to stir at RT for 16 h. Dioxane is removed under vacuum, the reaction mixture diluted with water (450 mL), pH is adjusted to 2 using IN HC1 and extracted with EtOAc (3 x 250 mL). The combined organic layers are washed with brine, dried over MgS04, filtered, concentrated under reduced pressure and dried to yield Fmoc- Val- Ala-OH. This product is suspended in dry DCM (25 ml), PABA (0.785 g, 6.38 mM) and EEDQ (1.971 g, 7.97mM) are added. The resulting mixture is treated under Argon with methanol until a clear solution is obtained. The reaction is stirred overnight and filtered. The filtrate is washed with diethyl ether (4x) and dried under high vacum to yield EC 1930 (1.85 g, 68%). 1H NMR (500 MHz, CD3OD): δ 7.79 (d, = 8.0 Hz, 2H), 7.65 (t, = 7.0 Hz, J2= 7.5 Hz, 2H), 7.54 (d, = 8.0 Hz, 2H), 7.38 (t, = 7.5 Hz, J2= 7.5 Hz, 2H), 7.33-7.24 (m, 4H), 4.54 (s, 2H), 4.48 (q, J = 14.0 Hz, J2= 7.0 Hz, 1H), 4.42-4.32 (m, 2H), 4.22 (t, J1=7.0 Hz, J2= 6.5 Hz, 1H), 3.94 (d, Ji= 7.0 Hz, 1H), 2.07 (m, 1H), 1.43 (d, Jl=7.5 Hz, 3H), 0.97 (d, Jl=7.0 Hz, 3H), 0.95 (d, Ji= 7.0 Hz, 3H); LCMS (ESI): (M + H)+= Calculated for C30H33N3O5, 516.24; found 516.24 |
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran | 4.4A The free carboxylic acid of the purified product (12) was then coupled to (4- aminophenyl)methanol (13), in the presence of 2 equivalents of EEDQ in THF to yield (9H-fluoren-9-yl)methyl ((S)-1 -(((S)-1 -((4-(hydroxymethyl)phenyl)amino)-1 - oxopropan-2-yl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (14). | |
1.85 g | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane Inert atmosphere; | To a solution of Val-Ala-OH (1 g, 5.31 mM) in water (40 ml) was added Na2CO3 (1.42 g, 13.28 mM) and cooled to 0°C before dioxane (40 mL) was added. A solution of Fmoc-Cl (1.44 g, 5.58 mM) in dioxane (40 mL) was added dropwise over 10 mm at 0°C. The reaction mixture was stirred at 0°C for 2h. Then the reaction mixture was allowed to stir at RT for 16 h. Dioxanewas removed under vacuum, the reaction mixture diluted with water (450 mL), pH was adjusted to 2 using iN HC1 and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure and dried to yield Fmoc-Val-Ala-OH. This product was suspended in dry DCM (25 ml), PABA (0.785 g, 6.38 mM) and EEDQ (1.971 g, 7.97mM) were added. The resulting mixture was treated underArgon with methanol until a clear solution was obtained. The reaction was stuffed overnight andfiltered. The filtrate was washed with diethyl ether (4x) and dried under high vacum to yieldEC1930 (1.85 g, 68%). ‘H NMR (500 MHz, CD3OD): 5 7.79 (d, J,= 8.0 Hz, 2H), 7.65 (t, J,=7.0 Hz, J2= 7.5 Hz, 2H), 7.54 (d, J,= 8.0 Hz, 2H), 7.38 (t, J,= 7.5 Hz, J2= 7.5 Hz, 2H), 7.33-7.24 (m, 4H), 4.54 (s, 2H), 4.48 (q, J,= 14.0 Hz, J2= 7.0 Hz, 1H), 4.42-4.32 (m, 2H), 4.22 (t,J,= 7.0 Hz, J2= 6.5 Hz, 1H), 3.94 (d, J,= 7.0 Hz, 1H), 2.07 (m, 1H), 1.43 (d, J,= 7.5 Hz, 3H),0.97 (d, J,= 7.0 Hz, 3H), 0.95 (d, J,= 7.0 Hz, 3H); LCMS (ESI): (M + H) = Calculated for C30H33N305, 516.24; found 516.24 |
20 g | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; | 3 Example 3 30 g of compound 3 (73 mmol) was suspended in dichloromethane (500 mL), then 4-aminobenzyl alcohol (11 g, 90 mmol), EEDQ (27 g, 113 mmol), and then methanol was added until the solution was clarified, stirred at room temperature overnight, filtered, solid methylene chloride After washing, the filtrate was concentrated to dryness to give crude compound 4, which was washed with methyl t-butyl ether to afford 20 g. |
20 g | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; | 3 Example 3 30g of compound 3 (73mmol) was suspended in 500mL of dichloromethane, 4-aminobenzyl alcohol (11g, 90mmol), EEDQ (27g, 113mmol) were added sequentially, and methanol was added until the solution was clear, stirred at room temperature overnight, filtered, solid dichloromethane wash,The filtrate was concentrated to dryness to obtain crude compound 4, which was washed with methyl tert-butyl ether to obtain 20 g of pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 3: piperidine / N,N-dimethyl-formamide / 0.02 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 4: triethylamine / dichloromethane; N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 4: triethylamine / dichloromethane; N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 4h; | 6.6A.1 Step 1. Synthesis of (9H-Fluoren-9-yl)methyl ((S)-3-methyl-1 -(((S)-1 -((4- ((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1 -oxopropan-2-yl)amino)-1 - oxobutan-2-yl)carbamate ("Fmoc-VAP-PNC") Procedure: (9H-Fluoren-9-yl)methyl ((S)-1 -(((S)-1 -((4- (hydroxymethyl)phenyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1 -oxobutan-2- yl)carbamate (21 ) (Fmoc-VAP-OH) (200 mg, 0.387 mmol) was dissolved in DMF (2 mL) and bis(4-nitrophenyl) carbonate (141 mg, 0.465 mmol) and DIPEA (200 mg, 1 .55 mmol) were added. The resulting solution was stirred for 4 h at room temperature. The reaction was concentrated under vacuum and purified by silica gel chromatography (DCM/EtOAc 0-100%). Concentration of the appropriate fractions gave (9H-fluoren-9-yl)methyl((S)-3-methyl-1 -(((S)-1 -((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1 -oxopropan-2-yl)amino)-1 - oxobutan-2-yl)carbamate (Fmoc-VAP-PNC) (22) (242 mg, 0.355 mmol, 92%). LC/MS 4.480 min (5-95% acetonitrile in water over 5 min), m/z 703.3 [M+Na]. |
74% | With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; | |
74% | With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 3.c Under a nitrogen atmosphere 4.2 mL N,N-diisopropylethylamine (DIPEA) (24.55 mmol, 3 eq) was added to a suspension of Fmoc-Val-Ala-PABOH 18 (4.22 g, 8.18 mmol, 1 eq) and bis-PNP carbonate (3.73 g, 12.28 mmol, 1.5 eq) in dry dichloromethane (84 mL). This yellow mixture was treated with 42 mL dry N,N-dimethylformamide (DMF) until a clear solution resulted and stirred over night at room temperature. Then, the solution was washed with water (60 mL) and the phases were separated. The aqueous layer was extracted four times with dichloromethane (a 30 mL) and the combined organic phases were dried and the solvent was removed under reduced pressure. The oily yellow residue was treated with diethyl ether (30 mL), sonicated and the precipitate was dried in vacuo to isolate product 19 as a white solid (4.1 g, 74%). 1H NMR (DMSO-d6): δ[ppm] 0.87 (d, 3H, J=6.8 Hz), 0.90 (d, 3H, J=6.7 Hz), 1.32 (d, 3H, J=7.0 Hz), 1.96-2.05 (m, 1H), 3.94 (t, 1H, J=7.3 Hz), 4.21-4.34 (m, 3H), 4.45 (p, 1H, J=7.0 Hz and 13.8 Hz), 5.25 (s, 2H), 7.31-7.47 (m, 7H), 7.55-7.77 (m, 6H), 7.89 (d, 2H, J=7.5 Hz), 8.21 (d, 1H, J=6.9 Hz), 8.30-8.33 (m, 2H), 10.10 (s, 1H). 13C NMR (DMSO-d6): δ[ppm] 18.4, 18.7, 19.6, 30.8, 47.1, 49.5, 60.4, 66.1, 70.7, 119.5, 120.5, 123.6, 125.8, 126.6, 127.5, 128.1, 129.9, 139.9, 141.1, 144.2, 144.3, 145.6, 152.4, 155.7, 156.6, 171.5, 171.7. |
65% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | |
7 g | With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4 Example 4 21 g of compound 4 (41 mmol) was suspended in 500 mL of dichloromethane.DIPEA (16 g, 126 mmol) was added in sequence.Di(p-nitrophenyl)carbonate (18.5 g, 69 mmol),Finally DMF was added until the solution was clear and stirred at room temperature overnight.DMF was distilled off under reduced pressure, and the viscous solid was washed with a small amount of methanol.Recrystallized several times with petroleum ether and ethyl acetate (or methyl tert-butyl ether).7 g of pure compound 5 were obtained. |
7 g | With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4 Example 4 21g of compound 4 (41 mmol) was suspended in 500 mL of dichloromethane, DIPEA (16 g, 126 mmol), bis (p-nitrobenzene) carbonate (18.5 g, 69 mmol) were added sequentially, and finally DMF was added until the solution was clear and stirred at room temperature overnight. DMF was distilled off under reduced pressure. The viscous solid was first washed with a small amount of methanol, and then recrystallized several times with petroleum ether and ethyl acetate (or methyl tert-butyl ether) to obtain 7 g of pure compound 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.8 g | With thionyl chloride In tetrahydrofuran at 20℃; for 1h; | III-1 Example 111-1. Synthesis of compound 24 [0206j To a stirred solution of Fmoc-VA-PAB (21) (Bioconjugate Chem., 2002, 13, 855-859) (9 g, 15 mmol) in THF (200 mL) was added thionyl chloride (18 mmol) dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for lh. TLC analysis (ethyl acetate/hexane, 1/1, v/v) showed the completion of the reaction. The solvents were removed under reduced pressure and the residue was washed with hexanes (100 mL) to give compound 22 as a slightly yellowish solid (8.8 g). |
With thionyl chloride In chloroform at 0 - 20℃; for 1h; | 1.2 Intermediate 2.5: Fmoc-Val-Ala-PAB-CI Intermediate 2.4 (0.100 g, 0.19 mmol) was dissolved in dry CHCI3 (10 mL) and was cooled to 0°C. SOCI2 (16 m, 0.213 mmol) was added dropwise to the solution and the mixture was stirred at rt for 1 h. The reaction was stopped by addition of a saturated solution of NaHC03. The layers were separated and the organic layer was dried over MgS04, filtered and concentrated in vacuo to provide 99 mg (95% yield) of crude Intermediate 2.5 which was used for the next step without any further purification. LC- MS: Rt = 5.76 min, m/z = 535 [M+H]+, m/z = 533 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane 2: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide / tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane 2: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N,N-dimethyl acetamide 2: 4-methyl-morpholine; N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate / N,N-dimethyl-formamide 3: N,N-dimethyl-formamide | ||
Multi-step reaction with 3 steps 1: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 2: N,N-dimethyl-formamide / 6 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C | ||
Multi-step reaction with 3 steps 1: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 2: N,N-dimethyl-formamide / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C |
Multi-step reaction with 3 steps 1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With piperidine In N,N-dimethyl-formamide at 20℃; for 1.25h; | 1 Synthesis of compound 2 To a colourless solution of 9-fluorenylmethyloxycarbonyl-valinyl-alanyl-4-aminobenzyl- alcohol (1) (502 mg, 973 pmol) in DMF (5.2 ml_) was added piperidine (260 pL, 2.63 mmol). The reaction mixture was stirred at room temperature for 75 minutes and then cone in vacuo. The residue was purified by silica gel chromatography (1 % 20% MeOH in DCM) affording the product 2 (88% pure by NMR, 333 mg, quant.) as a colorless oil. 1H-NMR (400 MHz, CDCI3) d (ppm) 7.42 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 4.45 (s, 2H), 4.40 (q, J = 7.0 Hz, 1 H), 3.05 (d, J = 5.6 Hz, 1 H), 1 .94-1 .80 (m, 1 H), 1 .33 (d, J = 7.2 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H). |
90% | With piperidine In N,N-dimethyl-formamide at 20℃; for 2h; | |
90% | With piperidine In N,N-dimethyl-formamide at 20℃; for 2h; | 4.3 3) Preparation of Val-Ala-PAB Fmoc-Val-Ala-PAB (4.0 g, 7.76 mM) was dissolved in DMF (40 mL), and piperidine (2 mL) was added after the dissolution was completed. The resulting mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (DCM/MeOH(v/v) =20:1) to obtain a white solid (2.1 g, 90% yield). 1H-NMR (400 MHz, DMSO-d6): δ 10.0(s, 1H), 8.18(s, 1H), 7.53(d, 2H), 7.24(d, 2H), 5.13(s, 1H), 4.48(t, 1H), 4.43(s, 1H), 3.00(d, 1H), 2.80(d, 1H), 1.92(m, 1H), 1.29(d, J=7.0 Hz, 3H), 0.85(dd, 6H). MS(ESI)m/z: 294.2 [M+H]+; 316.2 [M+Na]+. |
90% | With piperidine In N,N-dimethyl-formamide at 20℃; for 2h; | 4.3 3) Preparation of Val-Ala-PAB Fmoc-Val-Ala-PAB (4.0 g, 7.76 mM) was dissolved in DMF (40 mL), and piperidine (2 mL) was added after the dissolution was completed. The resulting mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (DCM/MeOH(v/v) =20:1) to obtain a white solid (2.1 g, 90% yield). 1H-NMR (400 MHz, DMSO-d6): δ 10.0(s, 1H), 8.18(s, 1H), 7.53(d, 2H), 7.24(d, 2H), 5.13(s, 1H), 4.48(t, 1H), 4.43(s, 1H), 3.00(d, 1H), 2.80(d, 1H), 1.92(m, 1H), 1.29(d, J=7.0 Hz, 3H), 0.85(dd, 6H). MS(ESI)m/z: 294.2 [M+H]+; 316.2 [M+Na]+. |
89% | With piperidine In N,N-dimethyl-formamide at 20℃; for 2h; | 3.2.7 Synthesis of (S)-2-amino-n-[(s)-1-[4-(hydroxymethyl) phenyl] amino}-1-oxypropane-2-yl]-3-methylbutylamide (10) Compound 8 (3g, 5.82mmol) was completely dissolved in 30mL of an N,N-dimethylformamide mixed solvent containing 5% piperidine, and the reaction was stirred at room temperature for 2h. At the end of the reaction, the reaction solution was concentrated under a reduced pressure and purified via column chromatography (dichloromethane: methanol=20:1, V/V). 1.52g of compound 10 were obtained at an 89% yield. 1H NMR (400MHz, DMSO-d6): δ 9.99 (s, 1H), 8.17 (d, J=7.4Hz, 1H), 7.53 (d, J=8.3Hz, 2H), 7.23 (d, J=8.2Hz, 2H), 5.12 (s, 1H), 4.55 - 4.33 (m, 3H), 3.00 (d, J=4.9Hz, 1H), 2.06 - 1.61 (m, 3H), 1.29 (d, J=7.0Hz, 3H), 0.82 (dd, J=40.5, 6.8Hz, 6H). ESI m/z: calculated for C15H23N3O3 293.2, found 294.2 [M+H]+. |
80.44% | With piperidine In dichloromethane at 20℃; for 0.5h; | I-15.4 Step 4. Synthesis of (S)-2-amino-N-((S)-l-((4-(hydroxymethyl)phenyl)amino)-l- oxopropan-2-yl)-3-methylbutanamide I-15e The solution of 9H-fluoren-9-ylmethyl N-[(lS)-l-[[(lS)-l-[[4-(hydroxymethyl) phenyl]carbamoyl]ethyl]carbamoyl]-2-methylpropyl]carbamate (2.60 g, 5.043 mmol, 1.00 eq) and piperidine (9.00 mL) in DCM (26.00 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC eluting with ACN in 5%-95% water to give 1.19 g (80.44%) of (2S)-2-amino-N-[(lS)-l-[[4- (hydroxymethyl)phenyl] carbamoyl] ethyl] -3 -methylbutanamide as a solid. LC-MS (ES, m/z): 294.20[M+H]+ |
72% | With piperidine In N,N-dimethyl-formamide at 20℃; for 1h; | |
In N,N-dimethyl acetamide | ||
With piperidine In N,N-dimethyl acetamide | 4.4A The product (14) was treated with 20% piperidine in DMA to yield (S)-2-amino-N-((S)-1 -((4- (hydroxymethyl)phenyl)amino)-1 -oxopropan-2-yl)-3-methylbutanamide (15). | |
With pyridine In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Inert atmosphere; | ||
With piperidine In N,N-dimethyl-formamide at 20℃; for 1.25h; | 1-2 To a colourless solution of 10 (502 mg, 973 mitioI) in DMF (5.2 ml_) was added piperidine (260 mI_, 2.63 mmol). The reaction mixture was stirred at room temperature for 75 minutes and then cone in vacuo. The residue was purified by silica chromatography (1 20% MeOH in DCM) affording the product 71 b (88% pure by NMR, 333 mg, quant.) as a colorless oil. 1 H NMR (400 MHz, CDCIs) d (ppm) 7.42 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 4.45 (s, 2H), 4.40 (q, J = 7.0 Hz, 1 H), 3.05 (d, J = 5.6 Hz, 1 H), 1.94-1 .80 (m, 1 H), 1 .33 (d, J = 7.2 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H). | |
With diethylamine In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; | ||
610 mg | With Ethane-1,2-diamine In dichloromethane at 20℃; for 1h; | 13.4 Step 4: Preparation of (S)-2-amino-N-((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxoprop-2-yl)-3-methylbutanamide. At room temperature, ethylenediamine (2 mL) was added to a solution of the compound 30-4 (1.1 g, 2.13 mmol) in dichloromethane (8 mL) and reacted for 1 h under stirring. Purification was performed on silica gel column chromatography to obtain the title compound (610 mg). ESI-MS (m/z): 294.2 [M+H]+ |
With diethylamine In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N,N-dimethyl acetamide 2: 4-methyl-morpholine; N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate / N,N-dimethyl-formamide | ||
Multi-step reaction with 2 steps 1: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 2: N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 2 steps 1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With pyridine In tetrahydrofuran at 0 - 20℃; for 1.5h; Inert atmosphere; | |
66% | With pyridine In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; | |
35% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Inert atmosphere; | Compound 22: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1 -(((S)-i -((4-((((4-nitrophenoxy)carbonyl)-oxy)methyl)phenyl)amino)-1 -oxopropan-2-yl)amino)-1 - oxobutan-2-yl )carbamate To a solution of compound 21 (1 .3 g, 2.52 mmol) in DMF (10 mL), was added, under Ar, DIEA (2.55 mL, 15.13 mmol), the solution was cooled down at 0°C before theaddition of 4-nitrophenyl chloroformate (1 .57 g, 7.56 mmol). The reaction medium was stirred for 2 h at RT. 20 mL of H20 were added and the medium was extracted twice with EtOAc (10 mL). The combined organic phases were washed with brine, dried over Mg504, filtered, concentrated in vacuo and purified by flash chromatography on 120 g of silica gel (gradient elution DCM/MeOH) to give 600 mgof compound 22 as a solid (35%).RMN 1H (400 MHz, ö in ppm, DMSO-d6): 0.86 (d, J = 7.0 Hz, 3 H); 0.89 (d, J =7.0 Hz, 3 H); 1 .31 (d, J = 7.0 Hz, 3 H); 1 .99 (m, 1 H); 3.91 (m, 1 H); 4.18 to 4.35 (m,3 H); 4.43 (m, 1 H); 5.24 (5, 2 H); 7.31 (t, J = 7.9 Hz, 2 H); 7.35 to 7.44 (m, 5 H); 7.56(d, J = 9.1 Hz, 2 H); 7.63 (d, J = 8.6 Hz, 2 H); 7.74 (m, 2 H); 7.88 (d, J = 7.9 Hz, 2 H);8.19 (d, J = 7.3 Hz, 1 H); 8.31 (d, J = 9.1 Hz, 2 H); 10.07 (5, 1 H). |
5.6 g | With pyridine In tetrahydrofuran; dichloromethane at 20℃; for 15h; | 3.1 Step 1: [4-[[(2S)-2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl- butanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate To a solution of 9H-fluoren-9-ylmethyl N-[(1S)-1-[[(1S)-2-[4-(hydroxymethyl)anilino]- 1-methyl-2-oxo-ethyl]carbamoyl]-2-methyl-propyl]carbamate (5.0 g, 9.7 mmol) in THF (20 mL) and DCM (10 mL) were successively added paranitrophenyl chlorocarbonate (4.1 g, 20.1 mmol) and pyridine (1.65 mL, 20.4 mmol). The reaction was stirred at room temperature for 15 h. A 10% aqueous solution of citric acid was added and the reaction mixture was extracted twice with AcOEt. The organic layer was washed with brine and dried over MgSO4. After evaporation under vacuum the solid was dissolved in a minimum amount of AcOEt and ether was added to precipitate the desired compound (5.6 g, 8.22 mmol). IR: (ν cm-1) 3350-3200, 1760;1690;1670;1630, 1523;1290.1H NMR (400 MHz, dmso-d6) δ ppm 10.07 (m, 1 H), 8.31 (d, 2 H), 8.19 (d, 1 H), 7.89 (d, 2 H), 7.74 (t, 2 H), 7.64 (d, 2 H), 7.57 (d, 2 H), 7.41 (m, 2 H), 7.41 (d, 2 H), 7.4 (m, 1 H), 7.32 (t, 2 H), 5.24 (s, 2 H), 4.43 (m, 1 H), 4.36-4.19 (m, 3 H), 3.92 (dd, 1 H), 2 (m, 1 H), 1.32 (d, 3 H), 0.9/0.87 (2d, 6 H). |
5.6 g | With pyridine In tetrahydrofuran; dichloromethane at 20℃; for 15h; | 3.1 Step 1: [4-[[(2S)-2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl- butanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate To a solution of 9H-fluoren-9-ylmethyl N-[(1S)-1-[[(1S)-2-[4-(hydroxymethyl)anilino]- 1-methyl-2-oxo-ethyl]carbamoyl]-2-methyl-propyl]carbamate (5.0 g, 9.7 mmol) in THF (20 mL) and DCM (10 mL) were successively added paranitrophenyl chlorocarbonate (4.1 g, 20.1 mmol) and pyridine (1.65 mL, 20.4 mmol). The reaction was stirred at room temperature for 15 h. A 10% aqueous solution of citric acid was added and the reaction mixture was extracted twice with AcOEt. The organic layer was washed with brine and dried over MgSO4. After evaporation under vacuum the solid was dissolved in a minimum amount of AcOEt and ether was added to precipitate the desired compound (5.6 g, 8.22 mmol). IR: (ν cm-1) 3350-3200, 1760;1690;1670;1630, 1523;1290.1H NMR (400 MHz, dmso-d6) δ ppm 10.07 (m, 1 H), 8.31 (d, 2 H), 8.19 (d, 1 H), 7.89 (d, 2 H), 7.74 (t, 2 H), 7.64 (d, 2 H), 7.57 (d, 2 H), 7.41 (m, 2 H), 7.41 (d, 2 H), 7.4 (m, 1 H), 7.32 (t, 2 H), 5.24 (s, 2 H), 4.43 (m, 1 H), 4.36-4.19 (m, 3 H), 3.92 (dd, 1 H), 2 (m, 1 H), 1.32 (d, 3 H), 0.9/0.87 (2d, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: pyridine / tetrahydrofuran / 1.5 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: pyridine / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: pyridine / tetrahydrofuran / 1.5 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; 4-dimethylaminopyridine / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / 0 - 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: pyridine / tetrahydrofuran / 1.5 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: pyridine / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / 0 - 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: piperidine / N,N-dimethyl-formamide / 2 h 2: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide | ||
Multi-step reaction with 2 steps 1: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide | ||
Multi-step reaction with 2 steps 1: piperidine / N,N-dimethyl-formamide / 2 h 2: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide |
Multi-step reaction with 2 steps 1: ethylenediamine / dichloromethane / 2 h / 20 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / dichloromethane / 4 h / 20 °C | ||
Multi-step reaction with 2 steps 1: piperidine / dichloromethane / 0.5 h / 20 °C 2: dicyclohexyl-carbodiimide / N,N-dimethyl-formamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.59% | With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 2h; | I-15.3 Step 3. Synthesis of (9H-fluoren-9-yl)methyl ((S)-l-(((S)-l-((4- (hydroxymethyl)phenyl)amino)- 1 -oxopropan-2-yl)amino)-3 -methyl- 1 -oxobutan-2- yl)carbamate I-15d Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of argon, was placed a solution of (2S)-2-amino-N-[4-(hydroxymethyl)phenyl]propanamide (5.00 g, 25.742 mmol, 1.00 eq), DCC (7.97 g, 38.613 mmol, 1.5 eq) and (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutanoic acid (10.48 g, 30.891 mmol, 1.2 equiv) in DMF (50.00 mL). The resulting solution was stirred for 2 hours at room temperature. After filtration, the filtrate was then quenched by the addition of 100 mL of water/ice and extracted with 2x100 mL of ethyl acetate, the organic layers were dried over anhydrous sodium sulfate and concentrated to obtain a residue, which was purified by Flash-Prep-HPLC eluting with ACN in 5-95% water to give 9.9 g (74.59%) of 9H-fluoren- 9-ylmethyl N-[(l S)-l-[[( IS)- 1 -[[4-(hydroxymethyl)phenyl]carbamoyl]ethyl]carbamoyl]-2- methylpropyl] carbamate as a solid. LC-MS (ES, m/z): 516.30 [M+H]+. |
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide | 2.21.3 2.21.3. (9H-fluoren-9-yl)methyl ((S)-l-(((S)-l-((4- (hydroxymethyl) phenyl)amino)-l-oxopropan-2-yl)amino)-3- methyl-l-oxobutan-2-yl)carbamate To a solution of Example 2.21.2 (5 g) in N,N-dimethylformamide (100 mL) was added (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanoic acid (10.48 g) and 2-(lH- benzo[d] [l,2,3]triazol-l-yl)- l, l,3,3-tetramethylisouronium hexafluorophosphate(V) (14.64 g), and the reaction was stirred overnight. The solvent was evaporated, the residue was washed with dichloromethane, and the solids were filtered to give the crude product. | |
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 | 2.21.3 2.21.3. (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl) phenyl)amino)- 1-oxopropan-2-yl)amino)-3- methyl-1-oxohutan-2-yL)carbamate To a solution of Example 2.21.2 (5 g) in N,N-dimethylformamide (100 mL) was added (S)-2-((((9H- fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanoic acid (10.48 g) and 2-(1H- benzo[d] [1,2,3] triazol-1 -yl)-l ,1,3 ,3-tetramethylisouronium hexafluorophosphate(V) (14.64 g), and the reaction was stirred overnight. The solvent was evaporated, the residue was washed withdichloromethane, and the solids were filtered to give the crude product. |
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide | 2.21.3 2.21.3. (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl) phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate To a solution of Example 2.21.2 (5 g) in N,N-dimethylformamide (100 mL) was added (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanoic acid (10.48 g) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (14.64 g), and the reaction was stirred overnight. The solvent was evaporated, the residue was washed with dichloromethane, and the solids were filtered to give the crude product. | |
1.1 g | With benzotriazol-1-ol; 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 dichloromethane at 20℃; for 4h; | 13.3 Step 3: Preparation of (9H-fluoren-9-yl)-methyl((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-carbamate. At room temperature, (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-butyric acid (875 mg, 2.58 mmol), O-benzotriazolyl-tetramethyluronium hexafluorophosphate (1.45 g, 3.83 mmol), N,N-diisopropylethylamine (1.00 g, 7.74 mmol) and 1-hydroxybenzotriazole (525 mg, 3.89 mmol) were successively added to a solution of the compound 30-3 (503 mg, 2.58 mmol) in dichloromethane (2 mL) and reacted for 4 hours under stirring. Purification was performed on silica gel column chromatography to obtain the title compound (1.1 g). ESI-MS (m/z): 516.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 20 °C 2: piperidine / N,N-dimethyl-formamide / 2 h 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide | ||
Multi-step reaction with 3 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 20 °C 2: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide | ||
Multi-step reaction with 3 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / methanol / 20 °C 2: piperidine / N,N-dimethyl-formamide / 2 h 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide |
Multi-step reaction with 3 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane / 3 h / 20 °C 2: ethylenediamine / dichloromethane / 2 h / 20 °C 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / dichloromethane / 4 h / 20 °C | ||
Multi-step reaction with 3 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran / 2 h / 20 °C / Inert atmosphere 2: piperidine / dichloromethane / 0.5 h / 20 °C 3: dicyclohexyl-carbodiimide / N,N-dimethyl-formamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: pyridine / tetrahydrofuran / 1 h / -78 °C 2: tetrahydrofuran; dichloromethane / -78 - -20 °C | ||
Multi-step reaction with 2 steps 1: pyridine / tetrahydrofuran / 1 h / -78 °C 2: dichloromethane / -78 - -20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In tetrahydrofuran at -78℃; for 1h; | 1 EC2405 (550 mg, 2.6 mmol) is dissolved in DCM (10 mL), and MgS04(3 g) is added followed by dropwise addition of ethanolamine (0.16 mL, 2.6 mmol) in DCM (10 mL). The reaction is stirred at rt for 1 hr. Filtration and concentration under vacuum gave the oxazoline intermediate. In another flask, EC1930 (516 mg, 1.0 mmol) is dissolved in THF (40 mL) and pyridine is added (0.8 mL, 10 mmol). The solution is cooled to -78 °C, and diphosgene (0.16 mL, 1.5 mmol) is added. The reaction is stirred at -78 °C for lh, DCM (20 mL) and a solution of oxazolidine intermediate is added dropwise. The reaction mixture is allowed to warm to -20 °C over several hours. LC-MS and TLC showed product formation. The reaction mixture is concentrated with silica gel and purified by flash chromatography (120 gold Redisep column, 0-100% EtOAc in petroleum ether) to give EC2076 (0.59 g, 74%). LCMS (ESI): (M + H)+= Calculated for C44H53N509, 796.38; found 796.74. | |
With pyridine In tetrahydrofuran at -78℃; for 1h; | The proline derived aldehyde (550 mg, 2.6 mmol) was dissolved in DCM (10 mL), MgSO4 (3g) was added followed by dropwise addition of ethanolamine (0.16 mL, 2.6 mmol) in DCM (10mL) and was added to the EC2405 mixture. The reaction was stirred at rt for 1 hr. Filtration andconcentration under vacuum gave the oxazoline intermediate. In another flask, EC1930 (516mg, 1.0 mmol) was dissolved in THF (40 mL) and pyridine was added (0.8 mL, 10 mmol). Thesolution was cooled to -78 °C, and diphosgene (0.16 mL, 1.5 mmol) was added. The reaction was stirred at -78 °C for lh, DCM (20 mL) and a solution of oxazolidine intermediate was added dropwise. The reaction mixture was allowed to warm to -20 °C over several hours. LCMS and TLC showed product formation. The reaction mixture was concentrated with silica geland purified by flash chromatography (120 gold Redisep column, 0-100% EtOAc in petroleum ether) to give EC2076 (0.59 g, 74%). LCMS (ESI): (M + H) = Calculated for CH53N5O9, 796.38; found 796.74. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium carbonate / water; 1,4-dioxane / 18 h / 0 - 20 °C 2: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / methanol; dichloromethane / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium carbonate / water; 1,4-dioxane / 18 h / 0 - 20 °C 2: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium carbonate / water; 1,4-dioxane / 18 h / 0 - 20 °C 2: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / methanol / Inert atmosphere |
Multi-step reaction with 2 steps 1: sodium carbonate / water; 1,4-dioxane / 18 h / 0 - 20 °C 2: N-ethoxy-carbonyl-2-ethoxy-1,3-dihydroquinoline / methanol; dichloromethane / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: dicyclohexyl-carbodiimide; 1-hydroxy-pyrrolidine-2,5-dione / tetrahydrofuran / 16 h / 20 °C 1.2: 16 h / 20 °C 2.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 36 h / 20 °C | ||
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 1.2: 1 h / 20 °C 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h | ||
Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide / tetrahydrofuran / 0 - 20 °C 2: Sodium hydrogenocarbonate / tetrahydrofuran; 1,2-dimethoxyethane; lithium hydroxide monohydrate / 20 °C 3: N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate / tetrahydrofuran / 14 h / 20 °C |
Multi-step reaction with 2 steps 1.1: 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide / tetrahydrofuran / 16 h / 0 - 20 °C 1.2: 72 h / 20 °C 2.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 72 h / 20 °C / Darkness | ||
Multi-step reaction with 2 steps 1.1: dicyclohexyl-carbodiimide; 1-hydroxy-pyrrolidine-2,5-dione / tetrahydrofuran / 16 h / 20 °C 1.2: 16 h / 20 °C 2.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 36 h / 20 °C / Darkness | ||
Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide / tetrahydrofuran / 16 h / 20 °C 2: Sodium hydrogenocarbonate / tetrahydrofuran; 1,2-dimethoxyethane; lithium hydroxide monohydrate / 16 h / 20 °C 3: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 12 h / 20 °C / Darkness | ||
Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide / tetrahydrofuran / 20 °C 2: Sodium hydrogenocarbonate / tetrahydrofuran; lithium hydroxide monohydrate; diethyl ether / 72 h / 20 °C 3: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide / tetrahydrofuran / 20 °C 2: Sodium hydrogenocarbonate / lithium hydroxide monohydrate; 1,2-dimethoxyethane / 20 °C 3: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 20 °C | ||
Multi-step reaction with 3 steps 1.1: dicyclohexyl-carbodiimide / tetrahydrofuran / 2 h / 0 - 20 °C 2.1: Sodium hydrogenocarbonate / tetrahydrofuran; 1,2-dimethoxyethane; lithium hydroxide monohydrate / 16 h / 20 °C 3.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / ethyl acetate / 0.5 h / 0 °C 3.2: 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 2: N,N-dimethyl-formamide / 6 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 4 steps 1: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 2: N,N-dimethyl-formamide / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 4 steps 1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C 4: benzotriazol-1-ol; pyridine / dimethyl sulfoxide / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.7% | Stage #1: (S)-tert-butyl 2-formyl-4-methylenepyrrolidine-1-carboxylate; ethanolamine With magnesium sulfate In dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)- 1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate; trichloromethyl chloroformate With triethylamine; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; | 31.1 Step 1: Preparation of Compound 49. A suspension of Compound 25 (288 mg, 1.35 mmol), 2-ethanolamine (45 iL, 0.749 mmol), and MgSO4 (200 mg) in anhydrous CH2C12 (5.0 mL) was stirred at room temperature under argon for 1 h. The reaction mixture was passed through a sintered glass frit, and the filtrate was added to a pre-mixed solution of Compound 48 (386 mg, 0.749 mmol), diphosgene (55.0 tL, 0.457 mmol), and 1Pr2NEt (270 iL, 1.57 mmol) in anhydrous THF (20 mL) at 0°C.To the solution was added Et3N (105 iL, 0.749 mmol), and the reaction mixture was stirred at0°C under argon for 5 mm. The reaction mixture was allowed to warm to room temperature and stirred under argon for an additional 25 mm. The solution was then concentrated under reduced pressure and purified via silica chromatography (0 - 70%EtOAc/pet. ether) to yieldCompound 49 as a white solid (195 mg, 32.7%): LC/MS: (ESI-QMS): m/z = 796.47 (M + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.59 g | Stage #1: (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)- 1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate; trichloromethyl chloroformate With pyridine In tetrahydrofuran at -78℃; for 1h; Stage #2: tert-butyl (2S)-4-methylene-2-(oxazolidin-2-yl)pyrrolidine-1-carboxylate In tetrahydrofuran; dichloromethane at -20℃; | 7 Example 7: Synthesis of FA-PBD inhibitor (compound 25) Compound 20 (550 mg, 2.6 mmol) was dissolved in DCM (10 mL), and MgS04(3 g) was added followed by dropwise addition of ethanolamine (0.16 mL, 2.6 mmol) in DCM(10 mL). The reaction was stirred at rt for 1 hr. Filtration and concentration under vacuum gave5 the oxazoline intermediate. In another flask, Compound 18 (516 mg, 1.0 mmol) was dissolvedin THF (40 mL) and pyridine was added (0.8 mL, 10 mmol). The solution was cooled to -78 °C,and diphosgene (0.16 mL, 1.5 mmol) was added. The reaction was stirred at -78 °C for 1h,DCM (20 mL) and a solution of oxazolidine intermediate was added dropwise. The reactionmixture was allowed to warm to -20 °C over several hours. LC-MS and TLC showed product10 formation. The reaction mixture was concentrated with silica gel and purified by flashchromatography (120 gold Redisep column, 0-100% EtOAc in petroleum ether) to giveCompound 21 (0.59 g, 74%). LCMS (ESI): (M + Ht =Calculated for C44Hs3Ns09, 796.38;found 796.74.55 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With dmap In N,N-dimethyl-formamide for 2.33333h; | 4 Example 4-1. Synthesis of BCN-Val-Ala-PABC-calicheamicin 101 To a solution of Fmoc-Val-Ala-PAB-OH 10 (106 mg, 0.205 mmole) in DMF (1.0 ml_) was added DSC (52.7 mg, 0.205 mmole) and DMAP (12.2 mg, 99.9 mhhob) and the mixture was stirred for 2 h showing -66% conversion by LC-MS analysis. Additional DSC (32.0 mg, 0.125 mmole) was added and the reaction mixture was stirred for another 20 min. and then cone in vacuo. The resulting oil was dissolved in 1 ml_ of a mixture of DMF:DCM (1 :9) and purified by silica gel column chromatography by elution with 50 80% EtOAc in heptane, yielding the desired carbonate 11 (32.7 mg, 49.8 mmol, 24%) as a white solid. LCMS (EST) calculated for C35H36N409Na+ (M+Na+)679.24 found 679.04 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h; | In a flask under argon were added (9H-fluoren-9-yl)methyl ((S)-l-(((S)-l-((4- (hydroxymethyl)phenyl)amino)-l-oxopropan-2-yl)amino)-3-methyl-l-oxobutan-2- yl)carbamate (250 mg, 0.485 mmol), bis(perfluorophenyl) carbonate (382 mg, 0.970 mmol) and DMF (4 mL). Then, the mixture was cooled to 0C and N-ethyl-N- isopropylpropan-2-amine (127 mI, 0.727 mmol) was added dropwise. The reaction mixture was warmed up to rt and stirred for 2 h (check by LCMS). The crude was concentrated in vacuo. The crude was purified by automatic column chromatography (Interchim. solid deposit): DCM/MeOH: 9/1 . The desired fractions were concentrated in vacuo to give the desired compound 1.53, Yield 281 mg, 80 % as yellow oil. LCMS (ESI): 726.65 (MH+). |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 1h; | To a cooled (0C) solution of Fmoc-Val-Ala-PAB-OH (0.10 g, 0.19 mmol) in anhydrous DMF (1.0 mL) were added <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (0.21 g, 0.53 mmol) and DiPEA (50 pL, 37 mg, 0.29 mmol). The mixture was stirred for 1 h, poured out in a mixture of Et20 (10 mL) and heptane (10 mL), cooled to 0C, stirred for 1 h and filtered. The product was obtained as a white solid (95 mg, 0.13 mmol, 69%). 1 H NMR (400 MHz, DMSO-de) d (ppm) 10.15-10.10 (bs, 1 H), 8.27- 8.18 (m, 1 H), 7.93-7.84 (m, 2H), 7.79-7.60 (m, 4H), 7.50-7.26 (m, 6H), 5.34 (s, 2H), 4.48-4.38 (m, 1 H), 4.36-4.16 (m, 3H), 3.98-3.86 (m, 1 H), 2.07-1.92 (m, 1 H), 1.32 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H). 19F NMR (400 MHz, DMSO-de) d (ppm) -154.19 (d, J = 20 Hz, 2F), -157.34 (t, J = 23 Hz, 1 F), -162.21 (dd, J = 20 Hz, 23 Hz, 2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.68% | With NBS; triphenylphosphine In 1,4-dioxane; N,N-dimethyl-formamide at 20℃; for 3h; | 1.1.5.1.1 Step 1 : (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)- 1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (0.5 g, 0.97 mmol),1,4- dioxane (9.70 ml_, 0.97 mmol), triphenylphosphine (0.509 g,1.939 mmol), N- bromosuccinimide (0.345 g,1.939 mmol), and DMF (2.424 ml_, 0.97 mmol) were combined and stirred for 3 hours at RT. The reaction mix was concentrated and chromatographed to afford (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4- (bromomethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (116 mg, 0.201 mmol, 20.68 % yield). LC/MS (ESI, m/z),580.14 [M+H] |
With NBS; triphenylphosphine In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Cooling with ice; | ||
680 mg | With phosphorus tribromide In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 0.583333h; | 4.1.3 (9H-fluoren-9-yl)methyl((S)-1-(((S)-1-((4-(bromomethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2) A solution of 1 (1.00g, 1.94mmol) in anhydrous DMF (15mL) was cooled to 0 °C and PBr3520mg, 1.94mmoldiluted in anhydrous DCM was added dropwise. The reaction mixture was stirred at 0 °C for 20min, and then cool saturated NaHCO3 aqueous solution (6mL) was added to quench the reaction. The product was washed with cool water, brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give the crude product. Add an appropriate amount of anhydrous ether to the crude product and purification was performed by ultrasound and filtration to obtain the pure product as a white powder (680mg, yield: 61%), which was directly used in the next reaction. |
680 mg | With phosphorus tribromide In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 0.583333h; | 4.1.3 (9H-fluoren-9-yl)methyl((S)-1-(((S)-1-((4-(bromomethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2) A solution of 1 (1.00g, 1.94mmol) in anhydrous DMF (15mL) was cooled to 0 °C and PBr3520mg, 1.94mmoldiluted in anhydrous DCM was added dropwise. The reaction mixture was stirred at 0 °C for 20min, and then cool saturated NaHCO3 aqueous solution (6mL) was added to quench the reaction. The product was washed with cool water, brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give the crude product. Add an appropriate amount of anhydrous ether to the crude product and purification was performed by ultrasound and filtration to obtain the pure product as a white powder (680mg, yield: 61%), which was directly used in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 19 Example 19: Synthesis of 34 To a solution of 9-fluorenylmethyloxycarbonyl-valyl-alanyl-4-anninobenzylalcohol (33, 291 mg, 564 mitioI, 1.0 equiv.) in DMF (2.0 mL) was added N,N'-disuccinimidyl carbonate (292 mg, 1.14 mmol, 2.02 equiv.). To the resulting yellow suspension was added DiPEA (198 mI_, 1.20 mmol, 2.12 equiv.), generating a white suspension, which turned into a solution after a few minutes. The reaction mixture was stirred at room temperature for 50 minutes and then added portion wise to a stirred mixture of DCM (50 mL) and H2O (10 mL). The resulting suspension was filtered over a glass filter and the filtrate was then partially concentrated in vacuo to remove the DCM. Following the removal of DCM, Et20 (50 mL) was added to the mixture and the resulting biphasic system was filtered over the same glass filter used previously. The residue was washed with Et20 and then concentrated under high vacuum, affording 31 1 mg of a white solid. The solid was then suspended, ultrasonicated and decanted with H2O (2x), DCM (1x) and Et20 (2x) successively, affording the product 34 as a white solid (199 mg, -76% pure (qNMR), 230 mitioI, 41 %). LCMS (ESI+) calculated for C35H36N4Na09+ (M+Na+) 679.24, found 678.97. NMR (400 MHz, DMSO-de) d (ppm) 10.14 (s, 1 H), 8.23 (d, J = 6.8 Hz, 1 H), 7.91 (d, J = 7.6 Hz, 2H), 7.77 (t, J = 6.8 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.52-7.39 (m, 4H), 7.34 (t, J = 7.6 Hz, 2H), 5.77 (s, 1 H), 5.34 (s, 1 H), 4.44 (m, 1 H), 4.37-4.17 (m, 3H), 3.93 (t, J = 8.8 Hz, 1 H), 2.82 (bs, 3H), 2.06-1.94 (m, 1 H), 1.33 (d, J = 7.2 Hz, 3H), 0.89 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)- 1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate With oxalyl dichloride In dichloromethane; dimethyl sulfoxide at -80 - -70℃; for 1h; Inert atmosphere; Stage #2: With triethylamine In dichloromethane; dimethyl sulfoxide for 0.0833333h; Inert atmosphere; | 13 Example 13: Fmoc-Val-Ala-PAP-CHO (HDP 30.2623) In a three-necked flask, equipped with thermometer, dropping funnel and rubber septum, 20 ml dry dichloromethane was treated with (446 µl, 5.2 mmol) oxalyl chloride and the solution was cooled to -80 °C under argon atmosphere. DMSO (739 µl, 10.4 mmol) was added dropwise by a syringe via the rubber septum, maintaining the temperature below -70°C. After stirring for 15 min Fmoc-Val-Ala-PAB-OH (HDP 30.1419, 2.062 g, 4.0 mmol) dissolved in 20 ml dichloromethane was added dropwise through the dropping funnel over a period of 30 min and the mixture was stirred for another 30 min. Subsequently triethylamine (2.634 ml, 19.0 mmol) was added by a syringe and after 5 min the cooling bath was removed and reaction was allowed to warmup to room temperature. Then 25 ml water and 25 ml dichloromethane were added and the phases were separated. The aqueous phase was extracted with 20 ml dichloromethane and the combined organic phases were washed with 20 ml 0.2M citric acid, 3x20 ml water and 20 ml brine. After drying (MgSO4) the solvent was evaporated and the crude product (965 mg) was purified on silica gel with a gradient of 0-20% ethyl acetate in dichloromethane to yield 631 mg (31 %) product as an amorphous solid. 1H NMR (500 MHz, D6-DMSO) d 10.36 (s, 1H), 9.89 (s, 1H), 8.22 (d, J = 6.8 Hz, 1H), 7.91- 7.79 (m, 6H), 7.74 (t, J = 8.6 Hz, 2H), 7.45- 7.29 (m, 5H), 4.47 (p, J = 7.0 Hz, 1H), 4.37- 4.28 (m, 1H), 4.28- 4.19 (m, 2H), 3.95 (dd, J = 8.9, 7.0 Hz, 1H), 2.02 (h, J = 6.7 Hz, 1H), 1.35 (d, J = 7.1 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H). 13C NMR (126 MHz, D6-DMSO) d 191.35, 171.75, 171.03, 156.05, 144.40, 143.79, 143.69, 140.61, 131.30, 130.68, 127.52, 127.50, 126.93, 125.22, 119.96, 119.95, 118.76, 65.63, 59.86, 49.20, 46.64, 30.32, 19.06, 18.12, 17.70. MS (ESI+) found.: 536.25calc. for [M+Na]+: 536.22 (C30H31N3NaO5) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide for 72h; | 6 Synthesis of compound 14 To a solution of Fmoc-va-PAB-OH (1) (20 mg, 0.039 mmol) in anhydrous DMF (1 ml_) were added 13 (61 mg, 0.39 mmol) and p-toluenesulfonic acid hydrate (3.0 mg, 0.016 mmol). The mixture was stirred for 3 d and concentrated. The residue was purified by silica gel chromatography (30% 70% EtOAc in heptane). The desired product 14 was obtained as a colorless film (1 1 mg, 0.016 mmol, 42%). LCMS (ESI+) calculated for CssFUyNsNaCV (M+Na+) 696.33, found 696.36. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | Stage #1: (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)- 1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate With toluene-4-sulfonic acid In N,N-dimethyl-formamide for 0.416667h; Inert atmosphere; Molecular sieve; Stage #2: (cyclohexa-1enyloxy)acetic acid ethyl ester In N,N-dimethyl-formamide for 3h; Inert atmosphere; | 9 Under an atmosphere of nitro in a flame dried flask, to a solution of Fmoc-va-PAB-OH (1) (0.15 g, 0.29 mmol) in anhydrous DMF (4 ml_) was added activated molsieves (53 mg). The mixture was stirred for 30 min and 4-toluenesulfonic acid monohydrate (18 mg, 0.096 mmol) was added. The mixture was stirred for 25 min and 21 (0.27 g, 1 .4 mmol) was added. The mixture was stirred for 3 h and filtered. The residue was rinsed with anhydrous DMF, diluted with DCM and purified by silica gel chromatography (30% 70% EtOAc in heptane). The desired product 22 was obtained as a white solid (30 mg, 4.3 pmol, 15%). LCMS (ESI+) calculated for C4oH49N3NaC>8+ (M+Na+) 722.34 found 722.41 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
180 mg | In N,N-dimethyl-formamide at 70℃; for 1h; Inert atmosphere; | 8 Synthesis of compound 5: Compound 3 (250 mg, 1.21 mmol) was dissolved in 8.0 mL DCM, at room temperature, under an Argon atmosphere. The solution was cooled to 0 °C and Et3N (504 pL, 3.62 mmol) and triphosgene (717 mg, 1.21 mmol) were added sequentially. The resulting mixture was left to stir at 0 °C for 30 min and at room temperature for 2 hours. The solvent was evaporated under vacuum. The residue was dried under vacuum for 1 hour. A solution of FmocValAlaPAB alcohol (622 mg, 1.21 mmol) in anhydrous DMF (1.0 mL) was added dropwise. The mixture was heated at 70 °C for 1 hour. The mixture was left to cool to room temperature. It was then loaded directly onto a 100 g Ci8 Aq Isco column. Eluent: CH3CN and H2O (0.05% AcOH in both) eluted with 10% to 90% CH3CN over 30 min. The fractions containing product were combined, partially evaporated under vacuum, frozen, lyophilized. The product was obtained as a white solid (180 mg, 20% yield). MS (ESI, pos.): calc’d for C42H44N 09Na 771.3 (M+Na); found 771.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: phosphorus tribromide / dichloromethane; N,N-dimethyl-formamide / 0.58 h / 0 - 20 °C 2: N,N-dimethyl-formamide / 1 h / 20 °C 3: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 4: 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: phosphorus tribromide / dichloromethane; N,N-dimethyl-formamide / 0.58 h / 0 - 20 °C 2: N,N-dimethyl-formamide / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: phosphorus tribromide / dichloromethane; N,N-dimethyl-formamide / 0.58 h / 0 - 20 °C 2: N,N-dimethyl-formamide / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: phosphorus tribromide / dichloromethane; N,N-dimethyl-formamide / 0.58 h / 0 - 20 °C 2: N,N-dimethyl-formamide / 6 h / 20 °C 3: piperidine / tetrahydrofuran / 0.25 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: phosphorus tribromide / dichloromethane; N,N-dimethyl-formamide / 0.58 h / 0 - 20 °C 2: N,N-dimethyl-formamide / 6 h / 20 °C 3: piperidine / tetrahydrofuran / 0.25 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: phosphorus tribromide / dichloromethane; N,N-dimethyl-formamide / 0.58 h / 0 - 20 °C 2: N,N-dimethyl-formamide / 6 h / 20 °C 3: piperidine / tetrahydrofuran / 0.25 h / 20 °C 4: N,N-dimethyl-formamide / 0.17 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: phosphorus tribromide / dichloromethane; N,N-dimethyl-formamide / 0.58 h / 0 - 20 °C 2: N,N-dimethyl-formamide / 6 h / 20 °C 3: piperidine / tetrahydrofuran / 0.25 h / 20 °C 4: N,N-dimethyl-formamide / 0.17 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: phosphorus tribromide / dichloromethane; N,N-dimethyl-formamide / 0.58 h / 0 - 20 °C 2: N,N-dimethyl-formamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: phosphorus tribromide / dichloromethane; N,N-dimethyl-formamide / 0.58 h / 0 - 20 °C 2: N,N-dimethyl-formamide / 1 h / 20 °C 3: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / 0 - 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 5: trifluoroacetic acid / dichloromethane / 0.75 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.08 h / 20 °C 2.2: 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.08 h / 20 °C 2.2: 2 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 10 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C 4: benzotriazol-1-ol; pyridine / dimethyl sulfoxide / 16 h / 20 °C |