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CAS No. : | 79990-15-1 | MDL No. : | MFCD00062960 |
Formula : | C18H17NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QWXZOFZKSQXPDC-LLVKDONJSA-N |
M.W : | 311.33 | Pubchem ID : | 2724627 |
Synonyms : |
|
Num. heavy atoms : | 23 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 85.17 |
TPSA : | 75.63 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.03 cm/s |
Log Po/w (iLOGP) : | 2.43 |
Log Po/w (XLOGP3) : | 3.05 |
Log Po/w (WLOGP) : | 3.0 |
Log Po/w (MLOGP) : | 2.32 |
Log Po/w (SILICOS-IT) : | 2.53 |
Consensus Log Po/w : | 2.67 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.68 |
Solubility : | 0.0648 mg/ml ; 0.000208 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.3 |
Solubility : | 0.0154 mg/ml ; 0.0000496 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.89 |
Solubility : | 0.00396 mg/ml ; 0.0000127 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.61 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: Fmoc-Glu(Boc)-OH; C9H6F5N2OPol With benzotriazol-1-ol; diisopropyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide Stage #2: With trifluoroacetic acid In dichloromethane; N,N-dimethyl-formamide for 0.333333h; Stage #3: N-(fluoren-9-ylmethoxycarbonyl)glycine; 6-amino-N-(1-phenethylpiperidin-4-yl)-N-phenylhexanamide; N-Fmoc-Tyr-OH; N-(9-fluorenylmethoxycarbonyl)-D-alanine; N-[(9-fluorenyl)methoxycarbonyl]-4-chloro-L-phenylalanine Further stages; | General protocol for ligands 23-29 General procedure: 1g of MBHA resin (1.9 mmol/g) was swollen overnight in DCM. The Boc protecting group of the Glu side chain was removed with a cold (0 °C) solution of 50% TFA in DCM for 20 min (2 times). The resin was washed with DCM (5 mL, 5 times). The peptidyl-resin was then neutralized with a 6-fold excess of a 0.36 M solution of DIPEA in chloroform cooled down to -30 °C. The resin was then washed with DCM (5 mL, 3 times) followed by DMF (5 mL, 3 times). Excess of the solvent was removed, and the obtained resin was transferred to a high pressure glass vessel. A 3-fold excess of 1.7 M solution of 3-aminofentanyl in the DCM/DMF mixed solvent (1:1 v/v), HOBt, and DIC (1:1:1, 0.8 M in DMF) were then added, and the mixture was subjected to microwave irradiation at 80 °C for 30 min. The reaction mixture was then cooled to room temperature and stirred overnight using a shaker. The resin was washed with DCM (5 mL, 3 times) followed by DMF (5 mL, 3 times), and then a standard protocol was followed for the solid phase peptide synthesis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | General procedure: 1g of corresponding resin (substitutions: 1.6 mmol/g for the 2-chlorotrityl resin, 0.6 mmol/g for the lysine loaded Merrifield resin, and 1.9 mmol/g for the MBHA resin), was swollen overnight in DCM. The side chain protecting group (Fmoc or Alloc) of Lys on the peptidyl-resin was removed as previously described. A 6-fold excess of a 0.36 M solution of DIPEA in DCM cooled down to -50 C was then added dropwise under the stream of argon to a 3-fold excess of a 0.36 M solution of p-nitrochloroformate in DCM cooled down to -50 C. After stirring for a short time (ca 3 min) the obtained solution was added to the cold peptidyl-resin obtained by submerging the corresponding capped plastic syringe with the resin inside into liquid nitrogen to the point where the solvent freezing just started. The syringe with the reaction mixture was left on a shaker for 3 hours and allowed to warm to room temperature. The resin was then washed with DCM (5 mL, 3 times) followed by DMF (5 mL, 3 times). The excess of the solvent was removed, and the obtained resin was transferred to a high pressure glass vessel. A 3-fold excess of 1.7 M solution of 3-aminofentanyl in the DCM/DMF mixed solvent (1:1 v/v) was added to the resin, and the mixture was subjected to microwave irradiation at 80 C for 30 min. The reaction mixture was cooled to room temperature, and the resin was washed with DCM (5 mL, 3 times) followed by DMF (5 mL, 3 times). The standard solid phase peptide synthesis was continued as previously described. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: Fmoc-Glu(Boc)-OH; C6H13N2OPol With benzotriazol-1-ol; diisopropyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide Stage #2: With trifluoroacetic acid In dichloromethane; N,N-dimethyl-formamide for 0.333333h; Stage #3: Aminofentanyl; N-(fluoren-9-ylmethoxycarbonyl)glycine; N-(9-fluorenylmethoxycarbonyl)-D-alanine; N-(9-fluorenylmethoxycarbonyl)-D-leucine; FMoc-L-2,6-dimethyltyrosine; N-[(9-fluorenyl)methoxycarbonyl]-4-chloro-L-phenylalanine Further stages; | General protocol for ligands 23-29 General procedure: 1g of MBHA resin (1.9 mmol/g) was swollen overnight in DCM. The Boc protecting group of the Glu side chain was removed with a cold (0 °C) solution of 50% TFA in DCM for 20 min (2 times). The resin was washed with DCM (5 mL, 5 times). The peptidyl-resin was then neutralized with a 6-fold excess of a 0.36 M solution of DIPEA in chloroform cooled down to -30 °C. The resin was then washed with DCM (5 mL, 3 times) followed by DMF (5 mL, 3 times). Excess of the solvent was removed, and the obtained resin was transferred to a high pressure glass vessel. A 3-fold excess of 1.7 M solution of 3-aminofentanyl in the DCM/DMF mixed solvent (1:1 v/v), HOBt, and DIC (1:1:1, 0.8 M in DMF) were then added, and the mixture was subjected to microwave irradiation at 80 °C for 30 min. The reaction mixture was then cooled to room temperature and stirred overnight using a shaker. The resin was washed with DCM (5 mL, 3 times) followed by DMF (5 mL, 3 times), and then a standard protocol was followed for the solid phase peptide synthesis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Stage #1: (2S)-2-[9H-fluorene-9-ylmethoxycarbonylamino]-4-methoxybutanoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.15h; Stage #3: N-(fluoren-9-ylmethoxycarbonyl)glycine; Fmoc-Val-OH; Fmoc-Leu-OH; N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine; N-(9-fluorenylmethoxycarbonyl)-D-alanine; Fmoc-L-Gln(Trt)-OH; Fmoc-His(Trt)-OH; 3-[(S)-2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)ethyl]indole-1-carboxylic acid tert-butyl ester; 3-[2-[2-[2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid; 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Fmoc-Ser(tBu)-OH With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one; N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: With piperidine In 1-methyl-pyrrolidin-2-one for 0.333333h; Stage #3: N-(fluoren-9-ylmethoxycarbonyl)glycine; Fmoc-Pro-OH; N-Fmoc L-Phe; Fmoc-Tyr(tBu)-OH; N-(9-fluorenylmethoxycarbonyl)-D-alanine Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-(9-fluorenylmethoxycarbonyl)-D-alanine With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one; dichloromethane at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.416667h; Stage #3: Fmoc-Leu-OH; Fmoc-L-Lys(iPr,Boc)-OH; 9-fluorenylmethyloxycarbonyl-N(4)-(L-hydroorotyl)-4-aminophenylalanine; 9-fluorenylmethyloxycarbonyl-N(4)-(t-butylcarbamoyl)-D-4-aminophenylalanine; Fmoc-Pro-OH; Fmoc-Ser(tBu)-OH; N-(9-fluorenylmethoxycarbonyl)-D-alanine; trifluoroacetic acid; 9-fluorenylmethyloxycarbonyl-D-4-chlorophenylalanine; (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In aq. buffer at 37℃; for 10h; | ||
With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; Cooling with ice; | 1; 1.1-1; 1.1-2 Example 1-1 Quenching agent: AEHS (2-aminoethyl hydrogen sulfate), no addition of base HD-Ala-OH (0.0500 g, 0.561 mmol) was added with water (2.48 mL),NaHCO3 (0.106 g, 1.26 mmol, 2.24 eq.) was added, stirred under ice cooling,A THF solution (2.73 mL) in which Fmoc-OSu (0.371 g, 1.10 mmol, 1.96 eq.) was dissolved was added, and the mixture was stirred under ice-cooling for 1 hour. Subsequently, after stirring at room temperature for 1 hour, the solution was analyzed by LC-MS (analysis (1)). Analysis (1) One hour after sampling, AEHS (0.107 g, 0.755 mmol) was added as a quenching agent.The mixture was stirred again at room temperature, and after 1 hour and 3 hours from the addition of the quenching agent, the liquid was analyzed under LC-MS analysis conditions-1 (Analysis (2) and (3)). LC-MS analysis conditions-1Column: KINETEX Biphenyl, 1.7 μm, 2.1×100 mm (Shimadzu GLC, product number 00D-4628-AN)Mobile phase A: 0.1% formic acid aqueous solutionMobile phase B: acetonitrileFlow rate: 0.3mL/minColumn temperature: 40°CDetection wavelength: 254 nmGradient conditions: 0% B (0 min) → 20% B (3 min) → 95% B (15 min) → 20% B (20 min) → 20% B (30 min) | |
With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; Cooling with ice; | 1; 1.1-1; 1.1-2 Example 1-1 Quenching agent: AEHS (2-aminoethyl hydrogen sulfate), no addition of base HD-Ala-OH (0.0500 g, 0.561 mmol) was added with water (2.48 mL),NaHCO3 (0.106 g, 1.26 mmol, 2.24 eq.) was added, stirred under ice cooling,A THF solution (2.73 mL) in which Fmoc-OSu (0.371 g, 1.10 mmol, 1.96 eq.) was dissolved was added, and the mixture was stirred under ice-cooling for 1 hour. Subsequently, after stirring at room temperature for 1 hour, the solution was analyzed by LC-MS (analysis (1)). Analysis (1) One hour after sampling, AEHS (0.107 g, 0.755 mmol) was added as a quenching agent.The mixture was stirred again at room temperature, and after 1 hour and 3 hours from the addition of the quenching agent, the liquid was analyzed under LC-MS analysis conditions-1 (Analysis (2) and (3)). LC-MS analysis conditions-1Column: KINETEX Biphenyl, 1.7 μm, 2.1×100 mm (Shimadzu GLC, product number 00D-4628-AN)Mobile phase A: 0.1% formic acid aqueous solutionMobile phase B: acetonitrileFlow rate: 0.3mL/minColumn temperature: 40°CDetection wavelength: 254 nmGradient conditions: 0% B (0 min) → 20% B (3 min) → 95% B (15 min) → 20% B (20 min) → 20% B (30 min) |
With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; Cooling with ice; | 1; 1.1-1; 1.1-2 Example 1-1 Quenching agent: AEHS (2-aminoethyl hydrogen sulfate), no addition of base HD-Ala-OH (0.0500 g, 0.561 mmol) was added with water (2.48 mL),NaHCO3 (0.106 g, 1.26 mmol, 2.24 eq.) was added, stirred under ice cooling,A THF solution (2.73 mL) in which Fmoc-OSu (0.371 g, 1.10 mmol, 1.96 eq.) was dissolved was added, and the mixture was stirred under ice-cooling for 1 hour. Subsequently, after stirring at room temperature for 1 hour, the solution was analyzed by LC-MS (analysis (1)). Analysis (1) One hour after sampling, AEHS (0.107 g, 0.755 mmol) was added as a quenching agent.The mixture was stirred again at room temperature, and after 1 hour and 3 hours from the addition of the quenching agent, the liquid was analyzed under LC-MS analysis conditions-1 (Analysis (2) and (3)). LC-MS analysis conditions-1Column: KINETEX Biphenyl, 1.7 μm, 2.1×100 mm (Shimadzu GLC, product number 00D-4628-AN)Mobile phase A: 0.1% formic acid aqueous solutionMobile phase B: acetonitrileFlow rate: 0.3mL/minColumn temperature: 40°CDetection wavelength: 254 nmGradient conditions: 0% B (0 min) → 20% B (3 min) → 95% B (15 min) → 20% B (20 min) → 20% B (30 min) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-(9-fluorenylmethoxycarbonyl)-D-alanine With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 25℃; for 1h; Stage #2: With pyrrolidine In N,N-dimethyl-formamide for 0.0833333h; Stage #3: Fmoc-Leu-OH; Fmoc-L-Lys(iPr,Boc)-OH; 9-fluorenylmethyloxycarbonyl-N(4)-(L-hydroorotyl)-4-aminophenylalanine; 9-fluorenylmethyloxycarbonyl-N(4)-(t-butylcarbamoyl)-D-4-aminophenylalanine; Fmoc-Pro-OH; Fmoc-Ser(tBu)-OH; acetic anhydride; trifluoroacetic acid; N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine; 9-fluorenylmethyloxycarbonyl-D-4-chlorophenylalanine; (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid Further stages; | 1-7 Example- 1: Charged 50 g of Rink amide AM resin and 500 mF of DMF into the Peptide vessel. Stirred the resin for 10 min and solvent is removed by applying vacuum. For swelling of resin charged 500 mF of DMF and allowed resin to stir for 45 min. Removed solvent by applying vacuum. Charged solution of 2% of Pyrrolidine in DMF into peptide vessel and stir for 10 min to deprotect the Fmoc of Resin. Kaiser test indicated complete deprotection.Coupling of Amino acid: Charged solution of 32.68 g of Fmoc-D-Ala-OH, 16.08 g of HOBt.PhO and 16.44 mF of DIPC into 500 mF of DMF into peptide vessel and stirred for 1 hr at 25+5°C. Kaiser test indicated complete coupling of N-protected amino acid.Deprotection of Amino acid: Charged 500 mF of solution of 2% Pyrrolidine in DMF into peptide vessel and stirred for 5 min. Removed the solvent by applying vacuum and repeated second deprotection for 10 min. Washed the resin with 4x500 mF of DMF and tested resin bead for deprotection. Repeated above coupling and deprotection procedure for sequential loading of Fmoc-Pro-OH, Fmoc-ILys(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-4Aph(tBu-cbm)-OH, Fmoc-L-4Aph(L-Hor)- OH, Fmoc-Ser(tBu)-OH, Fmoc-D-3-Pal-OH, Fmoc-D-Phe(4-Cl)-OH, Fmoc-D-2-Nal-OH.Acetylation: After deprotection of Fmoc-D-2-Nal-OH, charged solution of 12.5 mL of acetic anhydride and 10 mL of DIPEA in 500 mL of DMF into peptide vessel and stirred for 30 min. Removed the solvent by applying vacuum. Washed the resin with 3x500 mL of DML and tested resin bead for coupling.Cleavage of Degarelix form Resin: Charged 500 mL of TLA into a reaction vessel and cooled to l5+5°C. Charged resin slowly into the reaction vessel and stirred for 30 to 40 hrs at 25+5°C. Liltered the resin and the filtrate was concentrated under vacuum at 25+5°C. Charged concentrated residue into pre-chilled Di-isopropyl ether and stir for 1 hr at 25+5°C. Liltered the solid under vacuum and washed the solid with Di-isopropyl ether and the wet cake was dried under vacuum for 3 hrs. at 30°C. Obtained weight of Degarelix crude is between 80g to 90g. (purity by HPLC: 88.04%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The peptide was synthesized on a 0.250 mmol scale on CEM Liberty Blue, Microwave synthesizer using Fmoc/fBu chemistry on PS Rink-Amide MBHA resin, 0.32 mmol g-1. The assembly was performed using single-couplings using 4eq of Fmoc protected amino acid 0.2M in DMF, 4eq of 1 M Oxyme in DMF, 4eq of 0.5M L/,/V-diisopropylcarbodiimide (DIC) (double coupling for Y01 ). Fmoc deprotection cycles were performed using 20% (VA/) piperidine in DMF. (0856) The sequence of Fmoc protected amino acids and building blocks used are: (0857) 1. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-trityl-L-cysteine 2. (S)-1 ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpyrrolidine-2 -carboxylic acid (0858) 3. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (0859) 4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-trityl-L-histidine (0860) 5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (0861) 6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1 H-indol-3- yl)propanoic acid (0862) 7. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1 H-indol-3- yl)propanoic acid (0863) 8. (((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine (0864) 9. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine (0865) 10.3-(tritylthio)propanoic acid (0866) At the end of the assembly, the resin was washed with DMF, MeOH, DCM, Et20. The peptide was cleaved from solid support using 50 ml of TFA solution (v/v) (91 % TFA, 5% H2O, 4% TIPS) for approximately 1.5 hours, at room temperature. The resin was filtered, washed with TFA and solution concentrated to dryness and lyophilized. Lyophilization afforded Intermediate Compound Int. A (300mg), which was used as crude in the next step. (0867) LCMS anal calcd. C63H79F2N15013S2: 1356.53, found: 1356.9 (M+1 )+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The peptide was synthesized on a 0.250 mmol scale on CEM Liberty Blue, Microwave synthesizer using Fmoc/fBu chemistry on PS Rink-Amide MBHA resin, 0.32 mmol g_1. The assembly was performed using single-couplings using 4eq of Fmoc protected amino acid 0.2M in DMF, 4eq of 1 M Oxyme in DMF, 4eq of 0.5M A/,//-diisopropylcarbodiimide (DIC) (double coupling for Y01). Fmoc deprotection cycles were performed using 20% (V/V) piperidine in DMF. The sequence of Fmoc protected amino acids and building blocks used were: 1. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-trityl-L-cysteine 2. (S)-1((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpyrrolidine-2-carboxylic acid 3. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid 4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-trityl-L-histidine 5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid 6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1 H-indol-3- yl)propanoic acid 7. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1 H-indol-3- yl)propanoic acid 8. (((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine 9. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine 10. 3-(tritylthio)propanoic acid At the end of the assembly, the resin was washed with DMF, MeOH, DCM, Et2 H2O, 4% TIPS) for approximately 1.5 hours, at room temperature. The resin was filtered, washed with TFA and solution concentrated to dryness and lyophilized. Lyophilization afforded Intermediate Compound Int. A (300mg), which was used as crude in the next step. LCMS analysis was calculated for C63H79F2N15013S2: 1356.53, found: 1356.9 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The peptide was synthesized on a 0.250 mmol scale on CEM Liberty Blue, Microwave synthesizer using Fmoc/iBu chemistry on PS Rink-Amide MBHA resin, 0.32 mmol g_1. The assembly was performed using single-couplings using 4eq of Fmoc protected amino acid 0.2M in DMF, 4eq of 0.5M HATU in DMF, 4eq of 2M DIPEA (double coupling for Tyr). Fmoc deprotection cycles were performed using 20% (V/V) piperidine in DMF. The sequence of Fmoc protected amino acids and building blocks used were: ? (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(((1-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)methyl)phenyl)propanoic acid ? (S)-1 -(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid ? (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid ? N-(((9H-fluoren-9-yl)methoxy)carbonyl)-0-(tert-butyl)-L-threonine ? (2S,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-fluoropyrrolidine-2-carboxylic acid ? (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1 H-indol-3- yl)propanoic acid ? (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1 H-indol-3- yl)propanoic acid ? (((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine ? N-Allyloxycarbonyl glycine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The peptide was synthesized on a 0.250 mmol scale on CEM Liberty Blue, Microwave synthesizer using Fmoc/iBu chemistry on PS Rink-Amide MBHA resin, 0.32 mmol g_1. The assembly was performed using single-couplings using 4eq of Fmoc protected amino acid 0.2M in DMF, 4eq of 1 M Oxyme in DMF, 4eq of 0.5M A/,A/-diisopropylcarbodiimide (DIC) (double coupling for Y01 ). Fmoc deprotection cycles were performed using 20% (V/V) piperidine in DMF. The sequence of Fmoc protected amino acids and building blocks used were: 1. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-trityl-L-cysteine 2. (S)-1 ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpyrrolidine-2-carboxylic acid 3. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid 4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-trityl-L-histidine 5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid 6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1 H-indol-3- yl)propanoic acid 7. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1 H-indol-3- yl)propanoic acid 8. (((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine 9. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine 10. 3-(tritylthio)propanoic acid At the end of the assembly, the resin was washed with DMF, MeOH, DCM, Et20. The peptide was cleaved from solid support using 50 ml of TFA solution (v/v) (91 % TFA, 5% H20, 4% TIPS) for approximately 1 .5 hours, at room temperature. The resin was filtered, washed with TFA and solution concentrated to dryness and lyophilized. Lyophilization afforded Intermediate Compound Int. A (300mg), which was used as crude in the next step. LCMS analysis was calculated for C63H79F2N15013S2: 1356.53, found: 1356.9 (M+1 )+. | ||
The peptide was synthesized on a 0.250 mmol scale on CEM Liberty Blue, Microwave synthesizer using Fmoc/fBu chemistry on PS Rink-Amide MBHA resin, 0.32 mmol g_1. The assembly was performed using single-couplings using 4eq of Fmoc protected amino acid 0.2M in DMF, 4eq of 1 M Oxyme in DMF, 4eq of 0.5M A/,//-diisopropylcarbodiimide (DIC) (double coupling for Y01). Fmoc deprotection cycles were performed using 20% (V/V) piperidine in DMF. The sequence of Fmoc protected amino acids and building blocks used were: 1. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-trityl-L-cysteine 2. (S)-1 ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpyrrolidine-2-carboxylic acid 3. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid 4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-trityl-L-histidine 5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid 6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1 H-indol-3- yl)propanoic acid 7. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1 H-indol-3- yl)propanoic acid 8. (((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine 9. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine 10. 3-(tritylthio)propanoic acid At the end of the assembly, the resin was washed with DMF, MeOH, DCM, Et20. The peptide was cleaved from solid support using 50 ml of TFA solution (v/v) (91 % TFA, 5% H2O, 4% TIPS) for approximately 1.5 hours, at room temperature. The resin was filtered, washed with TFA and solution concentrated to dryness and lyophilized. Lyophilization afforded Intermediate Compound Int. A (300mg), which was used as crude in the next step. LCMS analysis was calculated for C63H79F2N15013S2: 1356.53, found: 1356.9 (M+1 )+. |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: N-(9-fluorenylmethoxycarbonyl)-D-alanine With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 0 - 10℃; for 2h; Stage #2: With 3-azapentane-1,5-diamine In N,N-dimethyl-formamide for 0.5h; Stage #3: Fmoc-Leu-OH; Fmoc-L-Lys(iPr,Boc)-OH; 9-fluorenylmethyloxycarbonyl-N(4)-(L-hydroorotyl)-4-aminophenylalanine; 9-fluorenylmethyloxycarbonyl-N(4)-(t-butylcarbamoyl)-D-4-aminophenylalanine; Fmoc-Pro-OH; Fmoc-Ser(tBu)-OH; 9-fluorenylmethyloxycarbonyl-D-2-naphthylalanine; acetic anhydride; 9-fluorenylmethyloxycarbonyl-D-4-chlorophenylalanine; (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid Further stages; | 1-12 Step 1 Rink Amide Resin Activation Fmoc-Rink amide AM resin (0.5 g) was placed in a peptide vessel and the resin was washed with 5 ml DMF 2 times and kept in DMF (5 ml) for 45 min and the solvent was then removed by applying vacuum. The washed resin was then deprotected with 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying vacuum and treated with 5% diethylenetriamine in DMF (5 ml) for 15 min. The vessel was emptied by applying vacuum and the resin was washed with DMF (5 ml). The vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). A solution of 0.326 gm Fmoc-Ala-OH (3.0 eq), 0.14 gm HOBT.H2O (3.0 eq) and 0.165 ml diisopropylcarbodimide (3.0 eq) was dissolved in DMF at 0-10° C. and allowed to activate for 10 min. This solution was charged into the peptide vessel, stirred for 2 hrs. and deprotected with 5% diethylenetriamine in DMF (5 ml) for 15 min. The vessel was emptied by applying vacuum and a second treatment 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying vacuum and the resin was washed with DMF (5 ml). The vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). Step 2 (0104) A solution of 0.354 gm Fmoc-Pro-OH (3.0 eq), 0.14 gm HOBT.H2O (3.0 eq) and 0.165 ml diisopropylcarbodimide (3.0 eq) was dissolved in DMF at 0-10° C. and allowed to activate for 10 min. This solution was then charged into the peptide vessel, stirred for 2 hrs. and washed with 5 ml DMF (4 times). Then it was deprotected with 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying vacuum and a second treatment 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applied vacuum and the resin washed with DMF (5 ml). The vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). (0105) Step 3 (0106) A solution of 0.536 gm Fmoc-Lys (ipr,Boc)-OH (3.0 eq), 0.14 gm HOBT.H2O (3.0 eq) and 0.165 ml diisopropylcarbodimide (3.0 eq) was dissolved in DMF at 0-10° C. and allowed to activate for 10 min and this solution charged into peptide vessel , stirred for 2 hrs., and washed with 5 ml DMF 4 times, and deprotected with 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and a second treatment 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applied vacuum and the resin washed with DMF (5 ml). The vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). (0107) Step 4 (0108) A solution of 0.371 gm Fmoc-Leu-OH (3.0 eq), 0.14 gm HOBT.H2O (3.0 eq) and 0.165 ml diisopropylcarbodimide (3.0 eq) was dissolved in DMF at 0-10° C. and allowed to activate for 10 min and this solution charged into a peptide vessel, stirred for 2 hrs., washed with 5 ml DMF 4 times, and deprotected with 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and second treatment 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applied vacuum and resin washed with DMF (5 ml). The vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). (0109) Step 5 (0110) A solution of 0.351 gm Fmoc-DAph(tBuCbm)-OH (2.0 eq),0.107 gm HOBT.H2O (2.0 eq) and 0.11 ml diisopropylcarbodimide (2.0 eq) was dissolved in DMF at 0-10° C. and allowed to activate for 10 min and this solution charged into the peptide vessel, stirred for 2 hrs., washed with 5 ml DMF 4 times, and deprotected with 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and a second treatment of 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and the resin washed with DMF (5 ml). the vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). (0111) Step 6 (0112) A solution of 0.379 gm Fmoc-Aph(Hor)-OH (2.0 eq),0.107 gm HOBT.H2O (2.0 eq) and 0.11 ml diisopropylcarbodimide (2.0 eq) was dissolved in DMF at 0-10° C. and allowed to activate for 10 min and this solution charged into the peptide vessel, stirred for 2 hrs. and deprotected with 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and a second treatment 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and the resin washed with DMF (5 ml). The vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). (0113) Step 7 (0114) A solution of 0.402 gm Fmoc-Ser(tBu)-OH (3.0 eq),0.14 gm HOBT.H2O (3.0eq) and 0.165 ml diisopropylcarbodimide (3.0 eq) was dissolved in DMF at 0-10° C. and allowed to activate for 10 min and this solution charged into peptide vessel, stirred for 2 hrs., washed with 5 ml DMF 4 times, and deprotected with 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and a second treatment 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and the resin washed with DMF (5 ml). The vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). (0115) Step 8 (0116) A solution of 0.407 gm Fmoc-D-3-Pal-OH (3.0 eq), 0.14 gm HOBT.H2O (3.0 eq) and 0.165 ml diisopropylcarbodimide (3.0 eq) was dissolved in DMF at 0-10° C. and allowed to activate for 10 min and this solution charged into peptide vessel, stirred for 2 hrs., and washed with 5 ml DMF 4 times and deprotected with 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and a second treatment 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and the resin washed with DMF (5 ml). A vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). (0117) Step 9 (0118) A solution of 0.442 gm Fmoc-D-Phe (4-Cl)-OH (3.0 eq), 0.14 gm HOBT.H2O (3.0eq) and 0.165 ml diisopropylcarbodimide (3.0 eq) was dissolved in DMF at 0-10° C. and allowed to activate for 10 min and this solution charged in to peptide vessel, stirred for 2 hrs. washed with 5 ml DMF 4 times, and deprotected with 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and a second treatment 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and the resin washed with DMF (5 ml). The vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). (0119) Step 10 (0120) A solution of 0.459 gm Fmoc-D-2-Nal-OH (3.0 eq), 0.14 gm HOBT.H2O (3.0 eq) and 0.165 ml diisopropylcarbodimide (3.0 eq) was dissolved in DMF at 0-10° C. and allowed to activate for 10 min and this solution charged into peptide vessel, stirred for 2 hrs., washed with 5 ml DMF 4 times, and deprotected with 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and second treatment 5% diethylenetriamine in DMF 5 ml for 15 min. The vessel was emptied by applying a vacuum and resin washed with DMF (5 ml). A vessel was further washed with methanol (5 ml*2 times) and DMF (5 ml*2 times). (0121) Step 11 (0122) Acetic anhydride (0.125 gm) was dissolved in dichloromethane (MDC) at 0-10° C. and charged into peptide vessel. The vessel was stirred for 3 hours and washed with dichloromethane (MDC-5 ml*4 times) and Methyltertiarybutylether (MTBE-5 ml*2 times) simultaneously. (0123) Step 12 (0124) TFA (5 ml) was taken in RBF and cooled to 0-10° C. Above the resin bed was then charged into TFA solution. Reaction mixture was then stirred for 24 hrs. at room temperature. Solution was filtered and then washed with TFA (1 ml). Filtrate ml was then distilled out up to one volume under vacuum and below 35° C. Methyltertiarybutylether (MTBE) (30 ml) was taken in another RBF and cooled to 0-10° C. Residue was then charged in this solution and then stirred for 1 hr. and filtered. The compound was dried under vacuum at 35° C. for 6-8 hr. Purity of the crude was about 85%-95%. The compound was further purified using preparative HPLC to get highly pure compound, greater than about 85%-95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-(9-fluorenylmethoxycarbonyl)-S-trityl-L-cysteine With ethyl cyanoglyoxylate-2-oxime; diisopropyl-carbodiimide In N,N-dimethyl-formamide Automated synthesizer; Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1H-indol-3-yl)-propanoic acid; 3-(tritylthio) propanoic acid; Fmoc-(tBu)Asp-OH; Fmoc-Lys(tert-butoxycarbonyl); N-(9-fluorenylmethoxycarbonyl)-D-alanine; Fmoc-His(Trt)-OH; N-(9-fluorenylmethoxycarbonyl)-O-methyl-L-tyrosine; (S)-1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpyrrolidine-2-carboxylic acid; trifluoroacetic acid Further stages; | A Step A - Synthesis of Intermediate Compound Int-A The peptide was synthesized on a 0.250 mmol scale on CEM Liberty Blue, Microwave synthesizer using Fmoc/iBu chemistry on PS Rink-Amide MBHA resin, 0.32 mmol g 1. The assembly was performed using single-couplings using 4eq of Fmoc protected amino acid 0.2M in DMF, 4eq of 1M Oxyma in DMF, 4eq of 0.5M /V, /V-d i i sopropyl carbod i i m i dc (DIC) (double coupling for Y01). Fmoc deprotection cycles were performed using 20% (V/V) piperidine in DMF. (0611) The sequence of Fmoc protected amino acids and building blocks used are: (0612) 1. N-(((9H-fhioren-9-yl)methoxy)carbonyl)-S-trityl-L-cysteine (0613) 2. (S)-l((((9H-fhioren-9-yl)methoxy)carbonyl)amino)-2-methylpyrrolidine-2-carboxylic acid (0614) 3. (S)-2-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (0615) 4. N-(((9H-fhioren-9-yl)methoxy)carbonyl)-N-trityl-L-histidine (0616) 5. (S)-2-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (0617) 6. (S)-2-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)-3-(5-fhioro-lH-indol-3-yl)propanoic acid (0618) 7. (S)-2-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)-3-(5-fhioro-lH-indol-3-yl)propanoic acid (0619) 8. (((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine (0620) 9. N2-(((9H-fhioren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine (0621) 10. 3-(tritylthio)propanoic acid (0622) At the end of the assembly, the resin was washed with DMF, MeOH, DCM, Et20. The peptide was cleaved from solid support using 50 ml of TFA solution (v/v) (91% TFA, 5% H2O, 4% TIPS) for approximately 1.5 hours, at room temperature. The resin was filtered, washed with TFA and solution concentrated to dryness and lyophilized. Lyophilization afforded Intermediate Compound Int. A (300mg), which was used as crude in the next step. LCMS anal calcd. C63H79F2N15013S2: 1356.53, found: 1356.9 (M+l)+ |
A786176[ 2714333-90-9 ]
(((9H-Fluoren-9-yl)methoxy)carbonyl)-D-alanine-15N
Reason: Stable Isotope