Structure of Fmoc-4-Amc-OH
CAS No.: 188715-40-4
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CAS No. : | 188715-40-4 |
Formula : | C23H25NO4 |
M.W : | 379.45 |
SMILES Code : | O=C(C1CCC(CNC(OCC2C3=C(C4=C2C=CC=C4)C=CC=C3)=O)CC1)O |
MDL No. : | MFCD01862347 |
InChI Key : | MLMIBGARTUSGND-UHFFFAOYSA-N |
Pubchem ID : | 2756125 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 28 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.39 |
Num. rotatable bonds | 7 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 107.09 |
TPSA ? Topological Polar Surface Area: Calculated from |
75.63 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.05 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.05 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.42 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.44 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.63 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.72 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.6 |
Solubility | 0.00955 mg/ml ; 0.0000252 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-5.34 |
Solubility | 0.00173 mg/ml ; 0.00000455 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-6.03 |
Solubility | 0.000358 mg/ml ; 0.000000944 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.74 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
4.15 |
* 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 |
---|---|---|
83% | Stage #1: With sodium carbonate In 1,4-dioxane; water at 20℃; for 2.5 h; Stage #2: With hydrogenchloride In 1,4-dioxane; water |
Step 1: Dissolve 4-Aminomethyl-cyclohexanecarboxylic acid ((39); 1.15g, 7.30mmol) in 1,4-dioxane (12.0mL) and 10percent aqu. Na2CO3 (23.2mL) and add Fmoc-Cl (2.26g, 8.76mmol). Stir the reaction mixture for 2.5h at rt. Add 1M aqu HCl (42.0mL) to the mixture and extract with EtOAc (3 times). Wash the combined organic layers with 1M aqu HCl, water and brine, extract the combined aqu layers once again with EtOAc, dry the combined organic layers with Na2SO4 and remove solvent under reduced pressure. The left crude product is washed with ice cold EtOAc and dried in oil pump vacuum to obtain (40) as a white solid (2.28g, 83percent). No further purification. [M. Nichifor; E. H. Schacht; Tetrahedron;1994; 50; 12; 3747-3760]. 1H NMR (400MHz, CDCl3): 0.87-1.02 (br.m, 2 H); 1.34-1.52 (br.m, 4 H); 1.81 (br.d, 2 H, J 6Hz); 1.90-2.11 (br.s, 1 H); 2.12-2.35 (br.m, 1 H); 3.03 (Ψt, 2 H, J = 6.2Hz); 4.19 (br.Ψt, 1 H, J = 6.5Hz); 4.42 (br.Ψd, 2 H, J = 6.5Hz); 4.74 (br.s, 1 H); 7.30 (Ψt, 2 H, J = 7.4Hz); 7.38 (Ψt, 2 H, J = 7.4Hz); 7.57 (d, 2 H, J = 7.4Hz); 7.75 (d, 2 H, J = 7.4Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Aminomethylcyclohexane carboxylic acid (1) (20 g, 127 mmol) and sodium carbonate (13.6 g, 128 mmol) were dissolved in 600 mL of water, then a solution of FmocOSu (40 g, 118 mmol) was added over a period of 30 min with stirring. The mixture was stirred overnight, during which a large amount of white precipitate formed. The mixture was acidified to pH=3 with 1N HCl, then diluted with 2L of ethyl acetate. The organic layer was separated, washed with 5percent aqueous citric acid, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and cooled in a freezer overnight. The solid was filtered off, then the filtrate was concentrated to ca. 1L and cooled overnight. The solid was filtered and combined with the previously collected solid (2) then dried in a desiccator. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The Fmoc aminomethylcyclohexyl carboxylic acid (2) was taken up in 1L of dichloromethane. Oxalyl chloride (39 mL, 450 mmol) was added, followed by DMF (10 drops) and the mixture was stirred for 1 h. The mixture was concentrated under vacuum and the residue was dissolved in 1L of toluene, and a solution of sodium azide (18.4 g, 280 mmol) in 30 mL of water was added along with 3.4 g (12 mmol) of tetrabutylammonium azide. Due to low solubility, an additional 2L of toluene was added, and the mixture was stirred vigorously until the IR spectrum of an aliquot showed a peak for the acyl azide (2120 cm-1). The mixture was filtered, and the solid set aside (unreacted acid chloride). The filtrate was extracted with 5% aqueous citric acid (2×200 mL) and brine (200 mL) then the toluene solution was dried over anhydrous sodium sulfate and filtered. The solution was heated to reflux until the IR spectrum of an aliquot of the solution showed an isocyanate peak (2230 cm-1) and loss of the acyl azide peak. The solution was evaporated to give 31 g of solid. The solid was dissolved in dichloromethane (800 mL) and stirred with Wang resin (57 g, 54 mmol) and 4N HCl in dioxane (1.5 mL) was added. The mixture was stirred overnight then filtered. The resin (3) was washed with DMF (3×800 mL), dichloromethane (3×800 mL) and diethyl ether (3×800 mL) then dried in a vacuum desiccator. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Step 1: Dissolve 4-Aminomethyl-cyclohexanecarboxylic acid ((39); 1.15g, 7.30mmol) in 1,4-dioxane (12.0mL) and 10percent aqu. Na2CO3 (23.2mL) and add Fmoc-Cl (2.26g, 8.76mmol). Stir the reaction mixture for 2.5h at rt. Add 1M aqu HCl (42.0mL) to the mixture and extract with EtOAc (3 times). Wash the combined organic layers with 1M aqu HCl, water and brine, extract the combined aqu layers once again with EtOAc, dry the combined organic layers with Na2SO4 and remove solvent under reduced pressure. The left crude product is washed with ice cold EtOAc and dried in oil pump vacuum to obtain (40) as a white solid (2.28g, 83percent). No further purification. [M. Nichifor; E. H. Schacht; Tetrahedron;1994; 50; 12; 3747-3760]. 1H NMR (400MHz, CDCl3): 0.87-1.02 (br.m, 2 H); 1.34-1.52 (br.m, 4 H); 1.81 (br.d, 2 H, J 6Hz); 1.90-2.11 (br.s, 1 H); 2.12-2.35 (br.m, 1 H); 3.03 (Psit, 2 H, J = 6.2Hz); 4.19 (br.Psit, 1 H, J = 6.5Hz); 4.42 (br.Psid, 2 H, J = 6.5Hz); 4.74 (br.s, 1 H); 7.30 (Psit, 2 H, J = 7.4Hz); 7.38 (Psit, 2 H, J = 7.4Hz); 7.57 (d, 2 H, J = 7.4Hz); 7.75 (d, 2 H, J = 7.4Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; for 14h; | Step 2: Dissolve (40) (190mg, 0.5mmol) in DCM (0.5mL) and DMF (0.25mL) at rt in a pre-dried tube, add DIEA (0.52mL, 1.5mmol) and add this solution to 2-chlorotritylchlorid-polystyrene (82mg, 0.13mmol) which is preswollen before in DCM (0.15mL). Shake the reaction suspensions for 14h at rt. The resin is (41) washed with DCM/MeOH/DIEA (17+2+1, 3 times), DCM (once), DMF (3 times) and again DCM (twice) and dried in vacuum. [i.e. Novabiochem2000 Catalog;2000; S15-S18]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PSMA-i was synthesized manually using standard Fmoc chemistry. Generally, peptide was synthesized at 0.2 mmol scale starting from C-terminal Fmoc-rink amide MBHA resin. Fmoc-deprotection at each cycle was carried out using 20% pipperidine in DMF. Coupling reactions were caffied out using 3.3 equiv of Fmoc-amino acids in DMF activated with 3.3 equiv of HCTU and 5 equiv of diisopropylethylamine (DIPEA) in DMF. These steps were repeated each time with an amino acid added. After the peptide sequence Fmoc-Glu?-Amc-Ahx-Glu-Glu-Glu-Lys(Mtt) was built on the resin, the Fmoc group of Nterminal amino acid Glu? was deprotected by 20% pipperidine. Then, a chloroform solution containing 3 eq of H-Glu(OtBu)-OtBu mixed with 2.5eq of DIPEA were prepared. The solution is then added slowly to 0.25 eq triphosgene in chloroform over 10 minutes at room temperature. After 15 minute incubation to allow for isocyanate formation, the reaction mixture was mixed with Glu?-Amc-Ahx-Glu-Glu-Glu-Lys on rink amide resin pre-swollen in chloroform with 2.5 eq of DIPEA. After the reaction was complete, the resin was washed with DMF and then dichloromethane and dried. The peptide was cleaved from resin by TFA/water/triisopropylsilane (950:25:25). The cleaved peptide was purified by preparative HPLC. The products were ascertained by high resolution matrix-assisted laser desorption/ionization mass (MALDI-MS) spectra from an Applied Biosystem 4800 MALDI TOF/TOF Analyzer in positive ion mode. Retention time: 19.0 mm. MALDI MS:C48H74N10020, 1087.5 (found); 1087.1 (calculated). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | 2-Chlorotrityl resin 100-200 mesh 1.8 mmol/g (1, 11.9 g, 21.4 mmol) was left to swell in dry dichloromethane (80 ml) for 20 minutes. A solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 5.50 g, 14.3 mmol) and N,N-diisopropylethylamine (9.44 ml, 54.2 mmol) in dry dichloromethane (70 ml) was added to resin and the mixture was shaken for 4 hours. Resin was filtered and 10 treated with a solution of N,N-diisopropylethylamine (4.97 ml, 28.5 mmol) in methanol/dichloromethane mixture (4: 1, 2 x 5 min, 2 x 57 ml). Then resin was washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,Ndimethylformamide (3 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was 15 washed with N,N-dimethylformamide (3 x 80 ml), 2-propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 11.0 g, 28.5 mmol), 0-( 6-chloro-benzotriazol-1-yi)-N,N,N', N'-tetramethyluronium tetrafluoroborate (TCTU, 10.1 g, 28.5 mmol) and N,N-diisopropylethylamine (9.93 ml, 57.0 mmol) in N,N20 dimethylformamide (80 ml) was added to resin and mixture was shaken for 2 hours. Resin was filtered and washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,N-N,N-dimethylformamide (3 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 225 propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of (S)-2-(9Hfluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 1-tert-butyl ester (Fmoc-LGiu OtBu, 9.11 g, 21.4 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 7.60 g, 21.4 mmol) and N,N-diisopropylethylamine (6.71 ml, 38.5 mmol) in N,N-dimethylformamide (80 ml) was added to resin and mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (2 x 80 5 ml), dichloromethane (2 x 80 ml) and N,N-dimethylformamide (2 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 2propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of 4-[(9Hfluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid (<strong>[188715-40-4]Fmoc-Trx-OH</strong>, 10 9.11 g, 21.4 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 7.60 g, 21.4 mmol) and N,N-diisopropylethylamine (6.71 ml, 38.5 mmol) in N,N-dimethylformamide (80 ml) was added to resin and mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,N-dimethylformamide (2 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 2propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of dodecanedioic acid mono-tert-butyl ester (C12(0tBu)-OH, 6.13 g, 21.4 mmol), 0-(6chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 7.61 g, 20 21.4 mmol) and N,N-diisopropylethylamine (6.71 ml, 38.5 mmol) in dichloromethane/N,N-dimethylformamide mixture (4: 1, 80 ml) was added to resin and mixture was shaken for 1.5 hour. Resin was filtered and washed with N,Ndimethylformamide (6 x 80 ml), dichloromethane (4 x 80 ml), methanol (4 x 80 ml) and dichloromethane (7 x 80 ml). The product was cleaved from resin by treatment with 25 2,2,2-trifluoroethanol (80 ml) for 18 hours. Resin was filtered off and washed with dichloromethane (4 x 80 ml), dichloromethane/2-propanol mixture (1:1, 4 x 80 ml), 2propanol (2 x 80 ml) and dichloromethane (6 x 80 ml). Solutions were combined; solvent evaporated and crude product was purified by column chromatography (Silicagel 60, 0.040-0-063 mm; eluent: dichloromethane/methanol 1:0-9:1). The pure product (2) 30 was dried in vacuo and obtained as oil. Yield: 5.40 g (42%). RF (Si02, dichloromethane/methanol 9: 1): 0.30. 1H NMR spectrum (300 MHz, CDC13, dH): 7.45-7.31 (m, 1 H); 7.10-6.97 (m, 1 H); 6.716.60 (m, 1 H); 5.70-5.58 (m, 1 H); 4.43-4.31 (m, 1 H); 4.15 (s, 2 H); 4.01 (s, 2 H); 35 3.79-3.31 (m, 16 H); 3.13-3.08 (m, 2 H); 2.28-1.79 (m, 11 H); 1.71-1.51 (m, 4 H); 1.46 (s, 9 H); 1.44 (s, 9 H); 1.25 (bs, 12 H); 1.05-0.88 (m, 2 H).LC-MS purity: 100%. LC-MS Rt (Sunfire 4.6 mm x 100 mm, acetonitrile/water 50:50 to 100:0 + 0.1% FA): 2.16 min. LC-MS m/z: 903.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 2-Chlorotrityl resin 100-200 mesh 1.8 mmol/g (1, 11.9 g, 21.4 mmol) was left to swell in dry dichloromethane (80 ml) for 20 minutes. A solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 5.50 g, 14.3 mmol) and N,N-diisopropylethylamine (9.44 ml, 54.2 mmol) in dry dichloromethane (70 ml) was added to resin and the mixture was shaken for 4 hours. Resin was filtered and 20 treated with a solution of N,N-diisopropylethylamine (4.97 ml, 28.5 mmol) in methanol/dichloromethane mixture (4: 1, 2 x 5 min, 2 x 57 ml). Then resin was washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,Ndimethylformamide (3 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 2-propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 11.0 g, 28.5 mmol), 0-( 6-chloro-benzotriazol-1-yi)-N,N,N', N'-tetramethyluronium tetrafluoroborate 5 (TCTU, 10.1 g, 28.5 mmol) and N,N-diisopropylethylamine (9.93 ml, 57.0 mmol) in N,Ndimethylformamide (80 ml) was added to resin and mixture was shaken for 2 hours. Resin was filtered and washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,N-N,N-dimethylformamide (3 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 10 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 2propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of (S)-2-(9Hfluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 1-tert-butyl ester (Fmoc-LGiuOtBu, 9.11 g, 21.4 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 7.60 g, 21.4 mmol) and N,N-diisopropylethylamine (6.71 ml, 15 38.5 mmol) in N,N-dimethylformamide (80 ml) was added to resin and mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,N-dimethylformamide (2 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 220 propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of Fmoctranexamic acid (<strong>[188715-40-4]Fmoc-Trx-OH</strong>, 9.11 g, 21.4 mmol), 0-(6-chloro-benzotriazol-1-yi)N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 7.60 g, 21.4 mmol) and N,Ndiisopropylethylamine (6.71 ml, 38.5 mmol) in N,N-dimethylformamide (80 ml) was added to resin and mixture was shaken for 1 hour. Resin was filtered and washed with 25 N,N-dimethylformamide (2 x 80 ml), dichloromethane (2 x 80 ml) and N,Ndimethylformamide (2 x 80 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 80 ml). Resin was washed with N,N-dimethylformamide (3 x 80 ml), 2-propanol (2 x 80 ml) and dichloromethane (100 ml, 2 x 80 ml). Solution of hexadecanedioic acid mono-tert-butyl ester (C16(0tBu)-OH, 7.33 g, 21.4 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'tetramethyluronium tetrafluoroborate (TCTU, 7.61 g, 21.4 mmol) and N,Ndiisopropylethylamine (6.71 ml, 38.5 mmol) in dichloromethane/N,N-dimethylformamide mixture (4: 1, 80 ml) was added to resin and mixture was shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (6 x 80 ml), dichloromethane (4 x 35 80 ml), methanol (4 x 80 ml) and dichloromethane (7 x 80 ml). The product was cleaved from resin by treatment with 2,2,2-trifluoroethanol (80 ml) for 18 hours. Resin was filtered off and washed with dichloromethane (4 x 80 ml), dichloromethane/2propanol mixture (1: 1, 4 x 80 ml), 2-propanol (2 x 80 ml) and dichloromethane (6 x 80 ml). Solutions were combined; solvent evaporated and crude product was purified by column chromatography (Silicagel 60, 0.040-0-063 mm; eluent: 5 dichloromethane/methanol 1:0-9:1).Intermediate (2) was dried in vacuo and obtained as oil. Yield: 8.20 g (80%). RF (Si02, dichloromethane/methanol 9: 1): 0.20. lH NMR spectrum (300 MHz, CDC13, dH): 7.44-7.33 (m, 1 H); 7.07-6.97 (m, 1 H); 6.7210 6.63 (m, 1 H); 5.70-5.59 (m, 1 H); 4.44-4.33 (m, 1 H); 4.15 (s, 2 H); 4.01 (s, 2 H); 3.76-3.32 (m, 16 H); 3.14-3.07 (m, 2 H); 2.38-1.77 (m, 11 H); 1.71-1.50 (m, 4 H); 1.46 (s, 9 H); 1.44 (s, 9 H); 1.25 (bs, 20 H); 1.05-0.87 (m, 2 H). LC-MS purity: 100%. LC-MS Rt (Sunfire 4.6 mm x 100 mm, acetonitrile/water 50:50 to 100:0 + 0.1% FA): 15 3.56 min. LC-MS m/z: 959.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Synthetic protocol: Wang Fmoc-Lys(Mtt) resin 0.26 mmol/g (1, 11.7 g, 3.05 mmol) was left to swell in 5 dichloromethane (100 ml) for 45 minutes. Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 90 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). A solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 2.35 g, 6.09 10 mmol), 0-( 6-chlorobenzotriazol-1-yi)-N, N,N', N' -tetramethyluronium tetrafluoroborate (TCTU, 2.17 g, 6.09 mmol) and N,N-diisopropylethylamine (2.12 ml, 12.2 mmol) in N,Ndimethylformamide (100 ml) was added to resin and the mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90 ml) and N,N-dimethylformamide (3 x 90 ml). Fmoc group was 15 removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 90 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of {2-[2-(9Hfluoren-9-ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 2.35 g, 6.09 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium 20 tetrafluoroborate (TCTU, 2.17 g, 6.09 mmol) and N,N-diisopropylethylamine (2.12 ml, 12.2 mmol) in N,N-dimethylformamide (100 ml) was added to resin and mixture was shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90 ml) and N,N-dimethylformamide (3 x 90 ml) to obtain intermediate 1. Fmoc group was removed by treatment with 20% piperidine in N,N25 dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 90 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 1-tert-butyl ester (Fmoc-LGiu-OtBu, 1.94 g, 4.57 mmol), 0-(6-chloro-benzotriazol-1-yi)N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 1.62 g, 4.57 mmol) and N,N30 diisopropylethylamine (1.43 ml, 8.23 mmol) in N,N-dimethylformamide (100 ml) was wo 2017/220706 PCT/EP2017/065342 72 added to resin and mixture was shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90ml) and N,Ndimethylformamide (3 x 90 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 90 ml). 5 Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of 4-[(9H-fluoren-9ylmethoxycarbonylamino )methyl]cyclohexanecarboxylic acid (<strong>[188715-40-4]Fmoc-Trx-OH</strong>, 1. 73 g, 4. 57 mmol), 0-( 6-chloro-benzotriazol-1-yi)-N,N,N', N'-tetramethyluronium tetrafluoroborate (TCTU, 1.62 g, 4.57 mmol) and N,N-diisopropylethylamine (1.43 ml, 8.23 mmol) in N,N10 dimethylformamide (100 ml) was added to resin and mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90ml) and N,N-dimethylformamide (3 x 90 ml) to obtain intermediate2. Fmoc group was removed by treatment with 20% piperidine in N,Ndimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 50 ml). Resin was washed 15 with N,N-dimethylformamide (3 x 50 ml), 2-propanol (3 x 50 ml) and dichloromethane (3 x 30 ml). Solution of octadecanedioic acid mono-tert-butyl ester (C18(0tBu)-OH, 0.85 g, 2.28 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 0.81 g, 2.28 mmol) and N,N-diisopropylethylamine (0. 72 ml, 4.11 mmol) in N,N-dimethylformamide (50 ml) was added to resin and mixture was 20 shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 50 ml), dichloromethane (3 x 50 ml) and N,N-dimethylformamide (3 x 50 ml). Mtt group was removed by treatment with 80% 1,1,1,3,3,3-hexafluoro-2-propanol in dichloromethane (2 x 10 min, 2 x 30 min, 4 x 50 ml). Resin was washed with dichloromethane (6 x 50 ml). Solution of bromoacetic acid (4.24 g, 30.5 mmol) and 25 N,N '-diisopropylcarbodiimide (DIC, 4.01 ml, 25.9 mmol) in N,N-dimethylformamide (50 ml) was added to resin and mixture was shaken for 45 minutes. Resin was filtered and washed with N,N-dimethylformamide (5 x 50 ml) and dichloromethane (10 x 50 ml). The product was cleaved from resin by treatment with trifluoroacetic acid (50 ml) for 1 hour. Resin was filtered off and washed with trifluoroacetic acid (1 x 25 ml) and 30 dichloromethane (2 x 30 ml). Solutions were combined and solvents were evaporated to dryness giving the compound as thick brownish oil. Yield: 2.18 mg (64%). 1H NMR spectrum (300 MHz, Ac0D-d4, 80C, dH): 4.72-4.55 (m, 2 H); 4.16 (s, 2 H); 4.12 (s, 2 H); 3.80-3.62 (m, 12 H); 3.58-3.44 (m, 4 H); 3.32 (t, J=6.8 Hz, 2 H); 3.15 35 (d, J=6.8 Hz, 2 H); 2.51-2.07 (m, 8 H); 2.01-1.77 (m, 6 H); ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Synthetic protocol: Wang Fmoc-Lys(Mtt) resin 0.26 mmol/g (1, 11.2 g, 2.90 mmol) was left to swell in dichloromethane (100 ml) for 45 minutes. Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 100 15 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). A solution of {2-[2-(9H-fluoren-9ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 2.23 g, 5.80 mmol), 0-(6-chlorobenzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 2.06 g, 5.80 mmol) and N,N-diisopropylethylamine (2.02 ml, 11.6 mmol) in N,N20 dimethylformamide (100 ml) was added to resin and the mixture was shaken for 1 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90 ml) and N,N-dimethylformamide (3 x 90 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 100 ml). Resin was washed with N,N-dimethylformamide (3 x 90 25 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of {2-[2-(9Hfluoren-9-ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (Fmoc-OEG-OH, 2.23 g, 5.80 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 2.06 g, 5.80 mmol) and N,N-diisopropylethylamine (2.02 ml, 11.6 mmol) in N,N-dimethylformamide (100 ml) was added to resin and mixture was 30 shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90ml), dichloromethane (3 x 90 ml) and N,N-dimethylformamide (3 x 90 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 100 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of (S)-2-(9H5 fluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 1-tert-butyl ester (Fmoc-LGiuOtBu, 1.85 g, 4.35 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU, 1.55 g, 4.35 mmol) and N,N-diisopropylethylamine (1.36 ml, 7.82 mmol) in N,N-dimethylformamide (100 ml) was added to resin and mixture was shaken for 1.5 hour. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 10 ml), dichloromethane (3 x 90ml) and N,N-dimethylformamide (3 x 90 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 100 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of <strong>[188715-40-4]4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid</strong> 15 (<strong>[188715-40-4]Fmoc-Trx-OH</strong>, 1.65 g, 4.35 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'tetramethyluronium tetrafluoroborate (TCTU, 1.55 g, 4.35 mmol) and N,Ndiisopropylethylamine (1.36 ml, 7.82 mmol) in N,N-dimethylformamide (100 ml) was added to resin and mixture was shaken for 2 hours. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90ml) and N,N20 dimethylformamide (3 x 90 ml). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 10 min, 1 x 30 min, 3 x 100 ml). Resin was washed with N,N-dimethylformamide (3 x 90 ml), 2-propanol (3 x 90 ml) and dichloromethane (3 x 90 ml). Solution of icosanedioic acid mono-tert-butyl ester (C20(0tBu)-OH, 1. 73 g, 4.35 mmol), 0-(6-chloro-benzotriazol-1-yi)-N,N,N',N'25 tetramethyluronium tetrafluoroborate (TCTU, 1.55 g, 4.35 mmol) and N,Ndiisopropylethylamine (1.36 ml, 7.82 mmol) in N,N-dimethylformamide (100 ml) was added to resin and mixture was shaken for 2 hours. Resin was filtered and washed with N,N-dimethylformamide (3 x 90 ml), dichloromethane (3 x 90 ml), N,Ndimethylformamide (3 x 90 ml) and dichloromethane (3 x 90 ml). Mtt group was 30 removed by treatment with 80% 1,1,1,3,3,3-hexafluoro-2-propanol in dichloromethane (2 x 10 min, 2 x 30 min, 4 x 100 ml). Resin was washed with dichloromethane (6 x 90 ml) and N,N-dimethylformamide (3 x 90 ml). Solution of bromoacetic acid (8.06 g, 58.0 mmol) and N,N '-diisopropylcarbodiimide (DIC, 7.60 ml, 49.3 mmol) in N,Ndimethylformamide (100 ml) was added to resin and mixture was shaken for 40 35 minutes. Resin was filtered and washed with N,N-dimethylformamide (5 x 90 ml) and dichloromethane (12 x 90 ml). The product was cleaved from resin by treatment with trifluoroacetic acid (100 ml) for 1 hour. Resin was filtered off and washed with trifluoroacetic acid (1 x 50 ml) and dichloromethane (7 x 70 ml). Solutions were combined and solvents were evaporated to dryness giving a thick brownish oil. Yield: 3.28 g (98%). 5 1H NMR spectrum (300 MHz, Ac0D-d4, 80 C, dH): 4.68 (dd, J=8.0 and 5.4 Hz, 1 H); 4.60 (dd, J=7.9 and 5.3 Hz, 1 H); 4.16 (s, 2 H); 4.12 (s, 2 H); 3.94 (s, 2 H); 3.81-3.61 (m, 12 H); 3.59-3.44 (m, 4 H); 3.32 (t, J=6.8 Hz, 2 H); 3.14 (d, J=6.8 Hz, 2 H); 2.491.79 (m, 15 H)... |
Tags: 188715-40-4 synthesis path| 188715-40-4 SDS| 188715-40-4 COA| 188715-40-4 purity| 188715-40-4 application| 188715-40-4 NMR| 188715-40-4 COA| 188715-40-4 structure
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