FMOC-DAB(ALOC)-OH

White to off-white powder

The peptide chain was elongated on CTC resin commencing with Fmoc-Dab(Dde)-OH[to CTC Resin (2 mmol, 2 g, 1.0 mmol/g) and Fmoc-Dab(Dde)-OH (806 mg, 1.6 mmol) in DCM (30 ml_), was added DIPEA (4.0 eq) and the reaction was mixed for 2 hours under nitrogen. MeOH (2 ml_) was added and the reaction was mixed for 30 minutes]. The reaction was drained and washed with DMF (x5) before the addition of 20% piperidine in DMF (for de blocking) with mixing for 30 minutes. The reaction was drained and washed with DMF (x5). Construction of the desired peptide sequence was continued using HATU (1.9-2.85 eq) and DIPEA (4-6.0 eq) in DMF (10 ml_) followed by 20% piperidine in DMF for each amino acid to afford H2N-[L-octylGly]-Dab(Dde)-Thr(OtBu)-Dab(Dde)-Dab(alloc)-Dab(Dde)-[D-Phe]-[L- octylGly]-Dab(Dde)-0-CTC-resin. The peptide was then treated with a mixture of 5:10:85 NMM: BOC20:DMF.At this point the resin was treated with Pd(PPhi ) CI2(0.15 eq) and PhSiFU (10 eq) in DCM. The resin was washed with DMF and MeOH to effect alloc deprotection and dried under nitrogen overnight. The peptide was further elongated as above with the required remaining amino acids. The peptide was treated with 1 %TFA/DCM (2 x 50 ml_) for 2 minutes and adjusted to pH=7 with DIPEA and diluted with DCM. TBTU (2 eq) and HOBt (2 eq) were added followed by DIPEA (2 eq), and the mixture was stirred for 1 hour to effect cyclisation. The reaction was washed with 5% aqueous HCI and concentrated in vacuo to afford Boc-[L- octylGly]-Dab(Dde)-Thr(OtBu)-Dab(Dde)-Dab*-Dab(Dde)-[D-Phe]-[L-octylGly]-Dab(Dde)- Dab(Dde)-Thr(OtBu)*.The crude peptide was treated with 92.5%TFA/2.5%H20/5%TIS (50 ml_) at room temperature and stirred for 3 hours. The reaction was filtered and the filtrate precipitated with cold isopropyl ether (300 ml_) and centrifuged (3 min at 3000 rpm). The crude peptide was washed with isopropyl ether (2 x 100 ml_), centrifuged, and purified using preparative HPLC (as described above using a gradient of between 35-65% MeCN in water (with 0.075% TFA) over 60 minutes) followed by lyophilisation to afford the title compound. LCMS (Method D): Rt = 5.02 minutes, ES+MS m/z 1055 [M+2]/2 and 703 [M+3]/3; theoretical mass: 2108The peptide chain was elongated on CTC resin commencing with Fmoc-Dab(Boc)-0-CTC- Resin.20% piperidine in DMF (for de-blocking) was added with mixing for 30 minutes. The reaction was drained and washed with DMF (x5). Construction of the desired peptide sequence was continued using HATU (1.9-2.85 eq) and DIPEA (4-6.0 eq) in DMF (10 ml_) followed by 20% piperidine in DMF for each amino acid to afford H2N-[L-octylGly]-Dab(Boc)-Thr(OH)-Dab(Boc)- Dab(Dde)-Dab(Boc)-[D-Phe]-[L-octylGly]-Dab(Boc)-0-CTC-resin. The peptide was then treated with a mixture of DCM and DIPEA (4 eq) with Cbz-CI (2 eq).At this point the resin was treated with 3% hydrazine hydrate in DMF to effect Dde deprotection. The resin was washed with DMF (x5) and the peptide was further elongated as above with the required remaining amino acids. The peptide was treated with 1 %TFA/DCM (2 x 50 ml_) for 2 minutes and adjusted to pH=7 with DIPEA and diluted with DCM. TBTU (2 eq) and HOBt (2 eq) were added followed by DIPEA (2 eq), and the mixture w stirred for 1 hour to effect cyclisation. The reaction was washed with 5% aqueous HCI and concentrated in vacuo to afford Cbz-[L-octylGly]-Dab(Boc)-Thr(OH)-Dab(Boc)-Dab*-Dab(Boc)-[D-Phe]-[L-octylGly]- Dab(Boc)-Dab(Boc)-Thr(OH)*.The crude peptide was treated with 4: 1 DMF:MeOH (50 ml_) and Pd(OH)2/C (50%, 2 g) was added under nitrogen. The suspension was purged with hydrogen several times and stirred under 15 psi hydrogen for 4 hours at 35C. The crude peptide was purified using preparative HPLC as described above using a gradient of between 55-95% MeCN in water (with 0.075% TFA) over 60 minutes to afford the title compound. LCMS (Method F): Rt = 10.06 minutes, ES+MS m/z 895 [M+2]/2 and 845 [M-Boc+2]/2; theoretical mass: 1788Fmoc protected resin 3 (100 mg, loading 0.62 mmol/g) was treated with a solution of 30% piperidine in DMF (2 mL) and shaken at rt for 15 min. The resin was drained and washed with DMF (× 3), MeOH (× 3) and DCM (× 3). The deprotection step was repeated. A solution of the corresponding amino acid (0.14 mmol, 2 eq.), DMF (0.29 mL), HCTU (0.5 M in DMF, 0.29 mL, 0.14 mmol, 2 eq.) and DIPEA (50 muL, 0.14 mmol, 4 eq.) was combined. After 1 min, the mixture was added to the resin. The resin was shaken for 30 min and then washed with DMF (× 3), MeOH (× 3) and DCM (× 3). The coupling step was repeated. An analytical sample was cleaved with TFA/Et3SiH/H2O (95:1:4) followed by LCMS analysis to confirm coupling with corresponding amino acid.The peptide chain was elongated on CTC resin commencing with Fmoc-Thr(OtBu)-OH [to CTC Resin (0.5 mmol, 0.5 g, 1.0 mmol/g) and Fmoc-Thr(OtBu)-OH (200 mg, 0.5 mmol, 1 eq) in DCM (5.0 mL), was added DIPEA (4 eq) and the reaction was mixed for 2 hours. MeOH(0.5 mL) was added and the reaction was capped and mixed for 30 minutes]. 20% piperidine in DMF was used for de-blocking and the desired amino acid sequence was constructed using HATU (2.85 eq) and DIPEA (6 eq) in DMF (2 mL) to afford nonanamideDab(Dde)-Thr(OtBu)Dab(Boc)-Dab(Alloc)-Dab(Dde)-[D-Phe]-Leu-Dab(Dde)-O-CTC-resin. At this point the resin was treated with Pd(PPh3)2C12 (0.1 eq) and PhSiH3 (10 eq) in DCM followed by resin washingwith DMF and MeOH to effect alloc deprotection and dried under nitrogen overnight. The peptide was further elongated as above with the required remaining amino acids. The peptide was cleaved from the resin with 1 %TFA/DCM (2 x 5 mL) for 2 minutes and adjusted to pH=7 with DIPEA in DCM. TBTU (2 eq) and HOBt (2 eq) were added followed by DIPEA (2 eq), and the mixture was stirred for 1 hour to effect cyclisation. The reaction was washed with 5%aqueous HCI and concentrated in vacuo to afford NonanamideDab(Dde)-Thr(OH)-Dab(Boc)The crude peptide was treated with 95%TFA/2.5%H20/2.5%TIS (5 mL) at room temperature and stirred for 30 minutes. The reaction was precipitated with cold isopropyl ether (50 mL) and centrifuged (3 mm at 3000 rpm). The crude peptide was washed with isopropyl ether (2 x 50 mL), centrifuged, and purifiedusing Preparative HPLC (Mobile phase A: 0.1% TFA in H20, B: H20) followed by lyophilisation to afford the scaffold without the linker. To a solution of the peptide in DCM, was added BocAhx-Ahx-OH (1.2 eq) and HBTU (1.2 eq) followed by DIPEA (2 eq) and the reaction was stirred for 30 minutes at room temperature. The reaction was washed twice with 5% HCI (aq) and concentrated in vacuo. The residue was treated with 20% TFAIDCM for 20 minutes andconcentrated in vacuo. The residue was purified using preparative HPLC (Mobile phase A:0.1% TFA in H20, B: H20) and lyophilised to afford the title compound.Rt = 8.2-9.3 minutes, ES+ MS mlz 1043.7 [M+2H]/2 and 696.3 [M+3H]/3; theoretical mass:2086.6The peptide chain was elongated on CTC resin commencing with Fmoc-Dab(Dde)-OH [to CTC Resin (2 mmol, 2 g, 1.0 mmol/g) and Fmoc-Dab(Dde)-OH (1.08 g, 2 mmol, 1.0 eq) in DCM (30 mL), was added DIPEA (4 eq) and the reaction was mixed for 2 hours. MeOH (2 mL) was added and the reaction was capped and mixed for 30 minutes]. 20% piperidine in DMF was used for de-blocking and the desired amino acid sequence was constructed using HATU (2.85 eq) and DIPEA (6 eq) in DMF (10 mL) to afford Boc(PEG8)-[L-octylGly]- Dab(Dde)-Thr(OtBu)- Dab(Dde)-Dab(Alloc)-Dab(Dde)-[D-Phe]-Leu-Dab(Dde)-0-CTC-resin. At this point the resin was treated with Pd(PP i3)2Cl2 (0.1 eq) and PhSiH3 (10 eq) in DCM followed by resin washing with DMF and MeOH to effect alloc deprotection and dried under nitrogen overnight. The peptide was further elongated as above with the required remaining amino acids. The peptide was treated with 1 %TFA/DCM (2 x 20 mL) for 2 minutes and adjusted to pH=7 with DIPEA and diluted with DCM. TBTU (2 eq) and HOBt (2 eq) were added followed by DIPEA (2 eq), and the mixture was stirred for 1 hour to effect cyclisation. The reaction was washed with 5% aqueous HCI and concentrated in vacuo to afford Boc-(PEG8)-[L-octylGly]-Dab(Dde)-Thr(OH)- Dab(Dde)-Dab*-Dab(Dde)-[D-Phe]-Leu-Dab(Dde)-Dab(Dde)-Thr(OH)*. The crude peptide was treated with 95%TFA/2.5%H20/2.5%TIS (5 mL) at room temperature and stirred for 30 minutes. The reaction was precipitated with cold isopropyl ether (300 mL) and centrifuged (3 min at 3000 rpm). The crude peptide was washed with isopropyl ether (2 x 100 mL), centrifuged, and purified using preparative HPLC (Mobile phase A: 0.1 % TFA in MeCN, B: H2O) followed by lyophilisation to afford the title compound. (0421) Rt = 10.6-11.9 minutes, ES+ MS m/z 1239.2 [M+2H]/2 and 826.4 [M+3H]/3; theoretical mass: 2477

Storage temperature 2-8°C

Molecular Weight:424.4
XLogP3:3.4
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:11
Exact Mass:424.16343649
Monoisotopic Mass:424.16343649
Topological Polar Surface Area:114
Heavy Atom Count:31
Complexity:632
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes