| 86% |
|
2-Chlorotrityl resin 100-200 mesh (42.6 g, 42.6 mmol) was left to swell in dry dichloromethane (205 mL) for 20 mm. A solution of {2-[2-(9H-fluoren-9- ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (13.7 g, 35.5 mmol) and N, N-diisopropylethylamine (23.5 mL, 135 mmol) in dry dichloromethane (30 mL) was added to resin and the mixture was shaken for 3 hrs. Resin was filtered and treated with a solution of N,N-diisopropylethylamine (12.4 mL, 70.9 mmol) in methanol/dichloromethane mixture (4:1, 250 mL, 2 x 5 mm). Then resin was washed with N,N-dimethylformamide (2 x 150 mL), dichloromethane (3 x 150 mL) and N,N-dimethylformamide (3 x 150 mL). Fmoc group was removed by treatment with 20% piperidine in dimethylformamide (1 x 5 mm, i x 30 mm, 2 x150 mL). Resin was washed with N,N-dimethylformamide (3 x 150 mL), 2-propanol (2 x 150 mL) and dichloromethane (200 mL, 2 x 150 mL). Solution of {2-[2-(9H-fluoren-9- ylmethoxycarbonylamino)-ethoxy]-ethoxy}-acetic acid (20.5 g, 53.2 mmol), O-(6-chloro- benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (TCTU, 18.9 g, 53.2 mmol)and N,N-diisopropylethylamine (16.7 mL, 95.7 mmol) in N,N-dimethylformamide (100 mL) and dichloromethane (50 mL) was added to resin and mixture was shaken for 1 hr. Resinwas filtered and washed with N,N-dimethylformamide (2 x 150 mL), dichloromethane (3 x150 mL) and N,N-dimethylformamide (155 mL). Fmoc group was removed by treatment with20% piperidine in dimethylformamide (1 x 5 mm, i x 30 mm, 2 x 150 mL). Resin was washedwith N,N-dimethylformamide (3 x 150 mL), 2-propanol (2 x 150 mL) and dichloromethane (200 mL, 2 x 150 mL). Solution of Fmoc-Glu-OtBu (22.6 g, 53.2 mmol), O-(6-chloro- benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (TCTU, 18.9 g, 53.2 mmol) and N,N-diisopropylethylamine (16.7 mL, 95.7 mmol) in N,N-dimethylformamide (155 mL) was added to resin and mixture was shaken for 1 hr. Resin was filtered and washed withN,N-dimethylformamide (2 x 150 mL), dichloromethane (2 x 150 mL) and N,Ndimethylformamide (150 mL). Fmoc group was removed by treatment with 20% piperidine in dimethylformamide (1 x 5 mm, i x 30 mm, 2 x 150 mL). Resin was washed with N,Ndimethylformamide (3 x 150 mL), 2-propanol (2 x 150 mL) and dichloromethane (200 mL, 2 x 150 mL). Solution of <strong>[843666-40-0]octadecanedioic acid mono-tert-butyl ester</strong> (19.7 g, 53.2 mmol), O-(6-chloro-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (TCTU, 18.9 g, 53.2 mmol) and N,N-diisopropylethylamine (16.7 mL, 95.7 mmol) in N,Ndimethylformamide/dichloromethane mixture (1:4, 200 mL) was added to resin. Resin was shaken for 2 hrs, filtered and washed with N,N-dimethylformamide (3 x 150 mL), dichloromethane (2 x 150 mL), methanol (2 x 150 mL) and dichloromethane (300 mL, 6 x 150 mL). The product was cleaved from resin by treatment with 2,2,2-trifluoroethanol (200 mL) for 19 hrs. Resin was filtered off and washed with dichloromethane (2 x 150 mL), 2- propanol/dichloromethane mixture (1:1,2 x 150 mL), 2-propanol (150 mL) and dichloromethane (2 x 150 mL). Solutions were combined; solvent evaporated and crude product was purified by flash column chromatography (Silicagel 60, 0.040-0.060 mm; eluent:dichloromethane/methanol 1:0-9:1). Pure product was dried in vacuo and obtained as yellow oil.Yield of 1 7-{(S)- 1 -tert-B utoxycarbonyl-3-[2-(2-[2-(2-carboxymethoxy-ethoxy)- ethylcarbamoyl]-methoxy}-ethoxy)-ethylcarbamoyl]-propylcarbamoyl}-heptadecanoic acid tert-butyl ester: 25.85 g (86%).RE (5i02, chloroform/methanol 85:15): 0.25.1 H NMR spectrum (300 MHz, CDCI3, dH): 7.38 (bs, 1 H); 7.08 (bs, 1 H); 6.61 (d,J=7.5 Hz, 1 H); 4.43 (m, 1 H); 4.15 (s, 2 H); 4.01 (s, 2 H); 3.78-3.39 (m, 16 H); 2.31 (t, J=6.9Hz, 2 H); 2.27-2.09 (m, 5 H); 2.01-1.84 (m, 1 H); 1.69-1.50 (m, 4 H); 1.46 (s, 9 H); 1.43 (s, 9H); 1.24(bs, 24 H).LC-MS m/z: 846.6 (M+H)+. |
| 1.1 g |
|
Starting resin: 50 2-Chlorotrityl resin, 1.60 mmol/g (0516) 1.0 g of the resin was swelled for 30 min in 51 DCM (10 ml). 1. Acylation with Fmoc-?-amino-3,6-dioxaoctanoic acid: (0517) 0.39 g (0.63 eq, 1.0 mmol) of Fmoc-?-amino-3,6-dioxaoctanoic acid (Fmoc-OEG-OH) was dissolved in DCM (15 ml) and was added to the resin. N,N-Diisopropylethylamine (DIEA) (0.44 ml, 2.5 mmol) was added dropwise. The reaction mixture was vortexed for 30 min. and then methanol (2 ml) was added and the mixture was vortexed for additional 15 min. The resin was filtered and washed with NMP (2×8 ml) and DCM (8×8 ml). (0518) 20% piperidine/NMP (8 ml) was added, standing 10 min. repeated once. Filtered and washed with NMP (2×8 ml), DCM (3×8 ml), and NMP (5×8 ml). A positive TNBS test gave red-coloured resins. 2. Acylation with Fmoc-?-amino-3,6-dioxaoctanoic acid: (0519) 0.78 g (2 eq, 2.0 mmol) of 54 Fmoc-?-55 amino-3,6-dioxaoctanoic acid was dissolved in NMP/51 DCM 1:1 (10 ml). 0.28 g (2.2 eq, 2.4 mmol) of HOSu was added followed by addition of 0.37 ml (2.2 eq, 2.4 mmol) of DIC. The reaction mixture was allowed to stand for 1 hour and was then added to the resin and finally 0.407 ml (2.2 eq) of 56 DIEA was added. The mixture was vortexed for 16 hours, filtered and washed with NMP (2×8 ml), DCM (3×8 ml), and NMP (5×8 ml). A positive TNBS test gave colourless resins. (0520) 20% 57 piperidine/NMP (10 ml) was added, standing 10 min. repeated once. Filtered and washed with NMP (2×8 ml), DCM (3×8 ml), and NMP (5×8 ml). A positive TNBS test gave red-coloured resins. Acylation with Fmoc-Glu-OtBu: (0521) 0.86 g (2 eq, 2.0 mmol) of 58 Fmoc-Glu-OtBu was dissolved in NMP/DCM 1:1 (10 ml). 0.32 g (2.2 eq, 2.4 mmol) of 59 HOBT was added followed by addition of 0.37 ml (2.2 eq, 2.4 mmol) of DIC. The reaction mixture was allowed to stand for 20 min and was then transferred to the resin and finally 0.407 ml (2.2 eq) of DIEA was added. The mixture was vortexed for 16 hours, filtered and washed with NMP (2×8 ml), DCM (3×8 ml), and NMP (5×8 ml). A positive TNBS test gave colourless resins. (0522) 20% piperidine/NMP (10 ml) was added, standing 10 min. repeated once. Filtered and washed with NMP (2×8 ml), DCM (3×8 ml), and NMP (5×8 ml). A positive TNBS test gave red-coloured resins. Acylation with Octadecanedioic Acid Mono Tert-Butyl Ester: (0523) 0.75 g (2 eq, 2.0 mmol) 60 Octadecanedioic acid mono tert-butyl ester was dissolved NMP/DCM 1:1 (10 ml). 0.32 g (2.2 eq, 2.4 mmol) HOBT was added followed by addition of 0.37 ml (2.2 eq, 2.4 mmol) of DIC. The reaction mixture was allowed to stand for 20 min and was then transferred to the resin and finally 0.41 ml (2.2 eq) of DIEA was added. The mixture was vortexed for 16 hours, filtered and washed with NMP (2×8 ml), DCM (3×8 ml), and NMP (5×8 ml). Cleavage with TFA: (0524) 8 ml of 5% 61 TFA/DCM was added to the resin and the reaction mixture was vortexed for 2 hours, filtered and the filtrate was collected. More 5% TFA/DCM (8 ml) was added to the resin, and the mixture was vortexed for 10 min, filtered and the resin was washed with DCM (2×10 ml). The combined filtrates and washings were pH adjusted to basic using about 800 ul of DIEA. The mixture was evaporated in vacuo affording an oil (3.5 g). 62 Diethylether (30 ml) was added and the not dissolved oil was separated by decantation and evaporated in vacuo. This afforded 1.1 g of 63 17-{(S)-1-tert-butoxycarbonyl-3-[2-(2-[2-(2-carboxymethoxyethoxyl)ethylcarbamoyl]methoxy}ethoxy)ethylcarbamoyl]propylcarbamoyl}heptadecanoic acid tert-butyl ester (alternative name: tert-butyl octadecandioyl-Glu(OEG-OEG-OH)-OTBU) as an oil. (0525) LC-MS (Sciex100 API): m/z=846.6 (M+1)+. |
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