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CAS No. : | 136552-06-2 | MDL No. : | MFCD01320843 |
Formula : | C19H17NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BXRZCDISGRVJCA-KRWDZBQOSA-N |
M.W : | 323.34 | Pubchem ID : | 2734468 |
Synonyms : |
|
Num. heavy atoms : | 24 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.26 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 91.87 |
TPSA : | 66.84 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.14 cm/s |
Log Po/w (iLOGP) : | 2.61 |
Log Po/w (XLOGP3) : | 3.0 |
Log Po/w (WLOGP) : | 2.71 |
Log Po/w (MLOGP) : | 2.55 |
Log Po/w (SILICOS-IT) : | 2.42 |
Consensus Log Po/w : | 2.66 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.77 |
Solubility : | 0.0543 mg/ml ; 0.000168 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.07 |
Solubility : | 0.0277 mg/ml ; 0.0000855 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.34 |
Solubility : | 0.0149 mg/ml ; 0.0000461 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.58 |
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 |
---|---|---|
In 1,4-dioxane; sodium carbonate; | C. To a solution of 0.50 g of (S)-2-azetidine carboxylic acid in 15 ml of 10% aqueous sodium carbonate solution was added 1.3 g of 9-fluorenylmethylchloroformate in 10 ml of dioxane, dropwise, while maintaining the temperature of the reaction mixture at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours, then poured into water and the aqueous solution washed with ether. The aqueous layer was cooled to 0 C. and adjusted to a pH of 2 with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered, and evaporated in vacuo to give (S)-N-(9-fluorenylmethoxycarbonyl)azetidine-2-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; | C. To a solution of 0.50 g of (S)-(-)-2-azetidine carboxylic acid in 15 ml of 10 aqueous sodium carbonate solution was added 1.3 g of 9-fluorenylmethyl chloroformate in 10 ml of dioxane, dropwise, while maintaining the temperature of the reaction mixture at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours, then poured into water and the aqueous solution was washed with ether. The aqueous layer was cooled to 0 C. and adjusted to a pH of 2 with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered, and evaporated in vacuo to give (S)-N-(9-fluorenylmethoxycarbonyl) azetidine-2-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A. When piperidine-2-carboxylic acid was substituted for (S)-2-azetidine carboxylic acid in Example 1C and treated in a manner similar to that of Example 1C, N-(9-fluorenylmethoxycarbonyl)piperidine-2-carboxylic acid was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 88To a suspension of l-<strong>[136552-06-2]Fmoc-L-azetidine-2-carboxylic acid</strong> (135 mg, 0.42 mmol, 2.9 equiv), and (2-(7-aza-1H-benzotriazole~l-yl)~ l ,l ,3,3-tetramethyluronium hexafluoro-phosphate) (164 mg, 0.43 mol, 3 equiv) in TIlF (1.5 mL) was added triethylamine (60 muL, 0.43 mmol, 3 equiv). After 30 rnin, aniline 2-6 (106 mg, 0.14 mmol, 1 equiv) was added. After 18 h, the reaction mixture was concentrated under reduced pressure. Preparative reverse phase HPLC of the resulting oil was performed on a Waters A utopurifi cation system using a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 rnL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; injection volume: 3 x 2.O mL (CHjCN); gradient: 80-? 100% B over 15 min; mass-directed fraction collection]. Fractions with the desired MW, eluting at 10.35- 12.0 min, were collected and freeze-dried to provide 131 mg of a yellow powder.To a solution of the above intermediate in CH2Cl2 (2 mL) was added piperidine (500 muL). After 30 min, the reaction solution was poured into aqueous pH 7 phosphate buffer and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification of the resulting crude oil via flash column chromatography on silica gel (Silicycle, 5 g, 0 to 5 to 10 to 50 % EtOAc in hexane gradient) provided 47.6 mg of the intermediate.Half of the above intermediate (24 mg) was dissolved in acetonitrile ( 1 mL), and an aqueous solution of HF (50%, 200 muL) was added. After 18.5 h, the reaction solution was poured into an aqueous K2HPO4 solution (2 5 g in 20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure.Palladium on carbon (10%, 12.5 mg) was added to a solution of the above intermediate in dioxane MeOH (1:1, 1 mL). The flask was fitted with a septum and evacuated and back-filled three times with hydrogen gas. Hydrogen gas was bubbled through the reaction solution for three minutes, and the reaction mixture was stirred under an atmosphere (balloon) of hydrogen gas for 4.5 h. The reaction mixture was filtered through celite to remove the palladium catalyst and concentrated under reduced pressure. Preparative reverse phase HPLC purification of the resulting oil was performed on a Waters Autopurification system using a Polymerx 10 mu RP-gamma 100 R column [30 x 21.20 mm, 10 micron, solvent A: 0.05N HCl in water, solvent B: CH3CN, injection volume: 3,0 mL (0.05N HCl in water); gradient elutiori with 0-?30% B over 10 min, then held at 100% for 5 min; mass-directed fraction collection]. Fractions with the desired MW, eluting at 9.8-1 1.25 min, were collected and freeze-dried. The resulting impure powder was purified via preparative reverse phase HPLC as above with gradient elution with I 5?50% B over 12 min, then held at 100% for 3 min, mass-directed fraction collection. Fractions with the desired MW, eluting at 6.5-8.0 min, were collected and freeze-dried to yield 2.0 mg of compound 88 (5%): 1H NMR (400 MHz, CD3OD) delta 8.25 (d, J = 11.0 Hz, 1 H), 5.29-5.24 (m, 1 H), 4.20-4.1 1 (m, 1 H), 4.09 (s, 1 H), 3.19-2.89 (m, 10 H), 2.69-2 56 (m, 1 H), 2.33-2. J 9 (m, 2 H), 1.68-1 56 (m, 1 H); MS (EST) m/z 531.30 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of BL5030-1, BL5030-2 and BL5030-4 using the CEM Liberty microwave peptide synthesizer; Synthesis of 2mmol of BL5030 peptides 1, 2 and 4 was performed on an automated peptide synthesizer in 2 batches of lmmol, using general Fmoc chemistry protocol: Rink amide methylbenzhydrylamine (MBHA) resin, 100-200, loading: 0.7mmol/g (714mg, lmmol) was added to a centrifuge tube and the tube attached to the synthesiser.The coupling cycle· Swelling: Initial swelling of the resin in 12 mL NMP, occurred for 120 minutes, prior to initialization of the reaction program on the synthesizer. Following transfer of the resin to the reaction vessel, under nitrogen pressure, swelling was continued for a further 15 minutes. Each coupling cycle includes the following steps: Fmoc deprotection, resin wash, coupling of amino acid and resin wash:? Fmoc Deprotection: Deprotection of the Fmoc group was achieved using a solution of 20% piperidine in NMP. The resin was mixed with 20 mL of this solution for 20 minutes and then with an additional 20 mL of this solution for a further 20 minutes.? Resin Wash: The resin was washed 4 times with a 20 mL portion of NMP for 2 minutes.? Coupling: The first 4 amino acids are common to all 3 peptides:Amino acid according to the sequence (3 equiv.; 1.988 g of Fmoc-HomoArg(pbf)OH for the first coupling cycle 1.379 g of Fmoc-D-TyrOH for the second coupling cycle, 970 mg of Fmoc-Aze-OH for the third coupling cycle or 1.181 g of Fmoc-Cha-OH for the fourth coupling cycle), in a 10 mL solution of 1 : 1 NMP:DMF, was transferred to the reaction vessel under nitrogen pressure. 0.5M HBTU/HOBt in DMF (3 eq., 6 ml) and 2MDIPEA in NMP (6 eq., 6 ml) were added to the resin. Nitrogen was bubbled through the reaction mixture for 60 minutes.For compound 1, a fifth amino acid was added on using the same conditions: 1.138 g of Fmoc-tranexamic acid in a 10 mL solution of 1 : 1 NMP:DMF.For compound 2, a fifth amino acid was added on using the same conditions: 1.446 g of Fmoc-L-Arg(pbf)OH) in a 10 mL solution of 1 : 1 NMP:DMF? Acetylation: An acetate cap was attached to compounds 2 and 4 only:Following the final deprotection, N-termini acetylation was carried out using 15 mL of10% acetic anhydride in NMP, and 1.5 mL of 2M DIPEA. The resin was mixed with this solution for 60 minutes.Cleavage from the resinOn completion of the peptide synthesis, the resin was transferred to a reaction vessel with a sintered glass bottom. The resin was washed with 20mL DCM and dried under vacuum. Afterwards, the peptide was cleaved from the resin by treatment with a solution of 95:2.5:2.5 TFA:TIS:H20 (30 mL) for 2 hours. The solution was concentrated toapproximately one third and the peptide was precipitated into cold diethyl ether. The ether solution was removed by decantation following centrifugation. The crude product was solubilised with H20:CH3CN 80:20 solution and lyophilized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of BL5030-3 and BL5030-5 using the CS Bio automated peptide synthesizer; Synthesis of 2mmol of BL5030 peptides 3 and 5 was performed on an automated peptide synthesizer using general Fmoc chemistry protocol: Rink amide methylbenzhydrylamine (MB HA) resin, 100-200, loading: 0.7mmol/g (714 mg, 1 mmol) was added to the reaction vessel of the synthesiser. The coupling cycle? Swelling: Initial swelling of the resin in 25 mL of NMP, occurred for 120 minutes, as the first step of the reaction program on the synthesizer. Each coupling cycle includes the following steps: Fmoc deprotection, resin wash, coupling of amino acid and resin wash:? Fmoc Deprotection: Deprotection of the Fmoc group was achieved using a solution of 20% piperidine in NMP. The resin was shaken with 25 mL of this solution for 5 minutes and then with an additional 20 mL of this solution for a further 20 minutes.? Resin Wash: The resin was washed 6 times with a 25 mL portion of NMP for 2 minutes.? Coupling: Both peptides have the same sequence of 5 amino acids:Amino acid according to the sequence (3 equiv.; 3.977 g of Fmoc-HomoArg(pbf)OH for the first coupling cycle, 2.758 g of Fmoc-D-TyrOH for the second coupling cycle, 1.940 g of Fmoc-Aze-OH for the third coupling cycle, 2.361 g of Fmoc-Cha-OH for the fourth coupling cycle and 2.277 g of Fmoc-tranexamic acid for the fifth coupling cycle) was dissolved in 0.5M HBTU/HOBt in DMF (3 eq., 12 ml) and the solution made up to 25 mL with NMP. This was transferred to the reaction vessel under nitrogen pressure. 1MDIPEA in NMP (6 eq., 12 ml) was added to the resin. The resin was mixed through repeated and continuous inversion of the reaction vessel for 60 minutes.? N-Termini guanidine group: A guanidine group was attached to compound 3:Following the final deprotection, 25 mL of 0.24M N,N'-Di-Boc-lH-pyrazole-l- carboxamidine in NMP (3 eq), and 12 mL of 1M DIPEA were added. The resin was mixed with this solution for 4 hours.Acetylation: An acetate cap was attached to compound 5:Following the final deprotection, N-termini acetylation was carried out using 25 mL of10% acetic anhydride in NMP, and 12 mL of 1M DIPEA. The resin was mixed with this solution for 60 minutes.Cleavage from the resinOn completion of the peptide synthesis, the resin was transferred to a reaction vessel with a sintered glass bottom. The resin was washed with 20 mL DCM and dried under vacuum. Afterwards, the peptide was cleaved from the resin by treatment with a solution of 95:2.5:2.5 TFA:TIS:H20 (30mL) for 2 hours. The solution was concentrated toapproximately one third and the peptide was precipitated into cold diethyl ether. The ether solution was removed by decantation following centrifugation. The crude product was solubilised with H20:CH3CN 80:20 solution and lyophilized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of BL5030-1, BL5030-2 and BL5030-4 using the CEM Liberty microwave peptide synthesizer; Synthesis of 2mmol of BL5030 peptides 1, 2 and 4 was performed on an automated peptide synthesizer in 2 batches of lmmol, using general Fmoc chemistry protocol: Rink amide methylbenzhydrylamine (MBHA) resin, 100-200, loading: 0.7mmol/g (714mg, lmmol) was added to a centrifuge tube and the tube attached to the synthesiser.The coupling cycle· Swelling: Initial swelling of the resin in 12 mL NMP, occurred for 120 minutes, prior to initialization of the reaction program on the synthesizer. Following transfer of the resin to the reaction vessel, under nitrogen pressure, swelling was continued for a further 15 minutes. Each coupling cycle includes the following steps: Fmoc deprotection, resin wash, coupling of amino acid and resin wash:? Fmoc Deprotection: Deprotection of the Fmoc group was achieved using a solution of 20% piperidine in NMP. The resin was mixed with 20 mL of this solution for 20 minutes and then with an additional 20 mL of this solution for a further 20 minutes.? Resin Wash: The resin was washed 4 times with a 20 mL portion of NMP for 2 minutes.? Coupling: The first 4 amino acids are common to all 3 peptides:Amino acid according to the sequence (3 equiv.; 1.988 g of Fmoc-HomoArg(pbf)OH for the first coupling cycle 1.379 g of Fmoc-D-TyrOH for the second coupling cycle, 970 mg of Fmoc-Aze-OH for the third coupling cycle or 1.181 g of Fmoc-Cha-OH for the fourth coupling cycle), in a 10 mL solution of 1 : 1 NMP:DMF, was transferred to the reaction vessel under nitrogen pressure. 0.5M HBTU/HOBt in DMF (3 eq., 6 ml) and 2MDIPEA in NMP (6 eq., 6 ml) were added to the resin. Nitrogen was bubbled through the reaction mixture for 60 minutes.For compound 1, a fifth amino acid was added on using the same conditions: 1.138 g of Fmoc-tranexamic acid in a 10 mL solution of 1 : 1 NMP:DMF.For compound 2, a fifth amino acid was added on using the same conditions: 1.446 g of Fmoc-L-Arg(pbf)OH) in a 10 mL solution of 1 : 1 NMP:DMF? Acetylation: An acetate cap was attached to compounds 2 and 4 only:Following the final deprotection, N-termini acetylation was carried out using 15 mL of10% acetic anhydride in NMP, and 1.5 mL of 2M DIPEA. The resin was mixed with this solution for 60 minutes.Cleavage from the resinOn completion of the peptide synthesis, the resin was transferred to a reaction vessel with a sintered glass bottom. The resin was washed with 20mL DCM and dried under vacuum. Afterwards, the peptide was cleaved from the resin by treatment with a solution of 95:2.5:2.5 TFA:TIS:H20 (30 mL) for 2 hours. The solution was concentrated toapproximately one third and the peptide was precipitated into cold diethyl ether. The ether solution was removed by decantation following centrifugation. The crude product was solubilised with H20:CH3CN 80:20 solution and lyophilized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were synthesized via standard solid-phase synthesis techniques starting with Fmoc-protected amino acids attached to Wang resin beads [37]. The C-terminal amino acid was deprotected and then coupled with an Fmoc-protected amino acid. The process was repeated until the desired peptide iscomplete. The peptide was then cleaved from the resin using trifluoroacetic acid and triisopropylsilane. The resulting peptides were dissolved in slightly acidified (1% HOAc) 50:50(v:v) H2O: CH3OH and diluted to ca.1×10-5 M. The following peptides were synthesized in this manner: AAXAA, AAAXA,AGXGA, AVXLG, and AXPAA, where X=(Aze, Pro, Pip, orNMeAla). In addition AAProPipA, AProPipAA, AA(DPro)AA, AV(D-Pip)LG, APipAProA, and AProAPipA were synthesized by this procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were synthesized via standard solid-phase synthesis techniques starting with Fmoc-protected amino acids attached to Wang resin beads [37]. The C-terminal amino acid was deprotected and then coupled with an Fmoc-protected amino acid. The process was repeated until the desired peptide iscomplete. The peptide was then cleaved from the resin using trifluoroacetic acid and triisopropylsilane. The resulting peptides were dissolved in slightly acidified (1% HOAc) 50:50(v:v) H2O: CH3OH and diluted to ca.1×10-5 M. The following peptides were synthesized in this manner: AAXAA, AAAXA,AGXGA, AVXLG, and AXPAA, where X=(Aze, Pro, Pip, orNMeAla). In addition AAProPipA, AProPipAA, AA(DPro)AA, AV(D-Pip)LG, APipAProA, and AProAPipA were synthesized by this procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were synthesized via standard solid-phase synthesis techniques starting with Fmoc-protected amino acids attached to Wang resin beads [37]. The C-terminal amino acid was deprotected and then coupled with an Fmoc-protected amino acid. The process was repeated until the desired peptide iscomplete. The peptide was then cleaved from the resin using trifluoroacetic acid and triisopropylsilane. The resulting peptides were dissolved in slightly acidified (1% HOAc) 50:50(v:v) H2O: CH3OH and diluted to ca.1×10-5 M. The following peptides were synthesized in this manner: AAXAA, AAAXA,AGXGA, AVXLG, and AXPAA, where X=(Aze, Pro, Pip, orNMeAla). In addition AAProPipA, AProPipAA, AA(DPro)AA, AV(D-Pip)LG, APipAProA, and AProAPipA were synthesized by this procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were synthesized via standard solid-phase synthesis techniques starting with Fmoc-protected amino acids attached to Wang resin beads [37]. The C-terminal amino acid was deprotected and then coupled with an Fmoc-protected amino acid. The process was repeated until the desired peptide iscomplete. The peptide was then cleaved from the resin using trifluoroacetic acid and triisopropylsilane. The resulting peptides were dissolved in slightly acidified (1% HOAc) 50:50(v:v) H2O: CH3OH and diluted to ca.1×10-5 M. The following peptides were synthesized in this manner: AAXAA, AAAXA,AGXGA, AVXLG, and AXPAA, where X=(Aze, Pro, Pip, orNMeAla). In addition AAProPipA, AProPipAA, AA(DPro)AA, AV(D-Pip)LG, APipAProA, and AProAPipA were synthesized by this procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Peptides were synthesized via standard solid-phase synthesis techniques starting with Fmoc-protected amino acids attached to Wang resin beads [37]. The C-terminal amino acid was deprotected and then coupled with an Fmoc-protected amino acid. The process was repeated until the desired peptide iscomplete. The peptide was then cleaved from the resin using trifluoroacetic acid and triisopropylsilane. The resulting peptides were dissolved in slightly acidified (1% HOAc) 50:50(v:v) H2O: CH3OH and diluted to ca.1×10-5 M. The following peptides were synthesized in this manner: AAXAA, AAAXA,AGXGA, AVXLG, and AXPAA, where X=(Aze, Pro, Pip, orNMeAla). In addition AAProPipA, AProPipAA, AA(DPro)AA, AV(D-Pip)LG, APipAProA, and AProAPipA were synthesized by this procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To the resin 13 (560 mg) in DMF (2.5 mL) were added a solutionof the appropriate Fmoc-protected amino acid (see Tables 1-3)(0.3 M), PyBOP (0.3 M) and HOBt (0.3 M) in dry DMF (4.2 mL). Thesuspensions were stirred for 3 min and then DIPEA (0.6 M) wasadded. The suspensions were stirred for 3 h under an argon atmosphereat rt. The resins were washed successively with DCM(150 mL), MeOH (120 mL), DCM (75 mL) and dried overnight undervacuum to give resins 14, each bearing an appropriate Fmoc-protectedamino acid. To the resins 14 (161 mg, 0.13 mmol) wereadded a solution of piperidine (20%, v/v) in DCM (2.1 mL) and themixtures were stirred for 1 h at rt. After filtration, the resins werewashed successively with DCM (50 mL), MeOH (45 mL), DCM(25 mL) and dried under vacuum to give resins 15. Portions(65 mg) of resins 15 were placed in reactor wells (12 mL) of anautomated synthesizer reaction block (40-well format) (AdvancedChemTech). To each well was added a solution of appropriate carboxylicacid (see Tables 1-3) (0.3 M), PyBOP (0.3 M) and HOBt 6-Cl(0.3 M) and DIPEA (0.6 M) in dry DMF (2 mL). The suspensionswere vortexed at 300 rpm over a period of 5 h under an argonatmosphere. The wells were then filtered to remove the reactivesolution from the resins 16 and washed successively with THF,DCM, MeOH and DCM. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The synthesis was carried out employing a Syro-peptide synthesizer (MultiSynTech) using 24-96 reaction vessels. In each vessel 0.04 mMol of the above resin was placed and the resin was swollen in CH2Cl2 and DMF for 15 min, respectively. The following reaction cycles were programmed and carried out: Unless indicated otherwise, the final coupling of an amino acid was followed by Fmoc deprotection by applying steps 1-3 of the above described reaction cycle. (1485) The appropriately protected amino acid building blocks are commercially available or can be synthesized as known in the art. (1486) Attachment of Carboxylic Acids or Amino Acids to Amino Group- or Carboxylic Group-Bearing Side Chains (1487) Procedure A (1488) Attachment of Carboxylic Acids or Amino Acids to Selectively Deprotected Linear Peptides on Resin: (1489) To remove alloc-protecting groups from amino functions or allyl-protecting groups from carboxy functions present in the resin bound peptide the latter (0.04 mMol) was swollen in freshly distilled CH2Cl2 for at least 15 min followed by adding 0.2 eq tetrakis(triphenyl-phosphine)palladium(0) (10 mM) in dry CH2Cl2 and 10 eq phenylsilane. After shaking the reaction mixture for 15 min at room temperature, the resin was filtered off and a fresh solution of reagents was added to repeat the procedure. Following subsequent washing of the resin with CH2Cl2, DMF and Et2O, the resin was swollen again in CH2Cl2 and the attachment of a carboxylic acid or appropriately protected amino acid was accomplished by subsequently adding a mixture of 3.6 eq of the desired acid and 3.6 eq HOAt dissolved in DMF and 3.6 eq DIC dissolved in DMF allowing the reaction mixture to stand for 1 h disrupted only by occasionally stirring. After filtration and washing of the resin three times with DMF, the coupling was completed by repeating the procedure with a fresh solution of a mixture of 3.6 eq of the same desired acid and 3.6 eq HOAt dissolved in DMF and a mixture of 3.6 eq HATU and 7.2 eq DIPEA in DMF. (1490) In case of amino group-bearing side chains the acids used to be coupled by the above described protocol were octanoic acid or N-Boc protected phenylalanine, in case of carboxy group-bearing side chains the acid coupled by the above described protocol was phenylalanine the carboxy group being protected by tBu. (1491) Cyclization and Work Up of Backbone Cyclized Peptides (1492) Cleavage of the Fully Protected Peptide Fragment (1493) After completion of the synthesis, the resin (0.04 mMol) was suspended in 1 mL (0.13 mMol, 3.4 eq) of 1% TFA in CH2Cl2 (v/v) for 3 minutes, filtered, and the filtrate was neutralized with 1 mL (0.58 mMol, 14.6 eq) of 10% DIEA in CH2Cl2 (v/v). This procedure was repeated three times to ensure completion of the cleavage. The filtrate was evaporated to dryness and a sample of the product was fully deprotected by using a cleavage mixture containing 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% triisopropylsilane (TIS) to be analyzed by reverse phase-HPLC (C18 column) and ESI-MS to monitor the efficiency of the linear peptide synthesis. (1494) Cyclization of the Linear Peptide (1495) The fully protected linear peptide (0.04 mMol) was dissolved in DMF (4 Mol/mL). Then 30.4 mg (0.08 mMol, 2 eq) of HATU, 10.9 mg (0.08 mMol, 2 eq) of HOAt and 28 mul (0.16 mMol, 4 eq) DIEA were added, and the mixture was vortexed at 25 C. for 16 hours and subsequently concentrated under high vacuum. The residue was partitioned between CH2Cl2 and H2O/CH3CN (90/10: v/v). The CH2Cl2 phase was evaporated to yield the fully protected cyclic peptide. (1496) Full Deprotection of the Cyclic Peptide (1497) The cyclic peptide obtained was dissolved in 3 mL of the cleavage mixture containing 82.5% trifluoroacetic acid (TFA), 5% water, 5% thioanisole, 5% phenol and 2.5% ethanedithiole (EDT). The mixture was allowed to stand at 25 C. for 2.5 hours and thereafter concentrated under vacuum. After precipitation of the cyclic fully deprotected peptide in diethylether (Et2O) at 0 C. the solid was washed twice with Et2O and dried. (1498) After purification of the crude products via preparative HPLC the peptides were 20 lyophilized (white powders) and analysed by the following analytical methods: Analytical Method A for Examples 1-17, 19, 39-49 (1499) Analytical HPLC retention times (RT, in minutes) were determined using a Ascentis Express C18 column, 50×3.0 mm, (cod. 53811-U-Supelco) with the following solvents A (H2O+0.1% TFA) and B (CH3CN+0.01% TFA) and the gradient: 0-0.05 min: 97% A, 3% B; 4.95 min: 3% A, 97% B; 5.35 min: 3% A, 97% B; 5.40 min: 97% A, 3% B. Flow rate=1.3 mL/min; UV_Vis=220 nm. Examples 34, 38, 45, 46 are shown in Table 1. The peptides were synthesized as follows: Starting resin was Fmoc-Pro-O-2-chlorotrityl resin, which was prepared as described above. To that resin Xaa12, finally at position 12, was grafted. The linear peptide was synthesized on solid support according to the procedure de... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The synthesis of peptidomimetics was carried out manually in syringe on the pre-loaded Fmoc-Arg(Pbf) Wang resin with capacity 0.39 mmol/g (0.5 g) following the standard Fmoc chemistry. Coupling of 2 eq protrcted amino acids (0.4 mmol) was done using 2 eq HATU (152 mg, 0.4 mmol) and 5 eq DIPEA (169 muL, 1 mmol) in DMF (5 mL). Completion of coupling was checked using Kaiser or chloranil test. Deprotection step was done using 20% piperidine in DMF.Protected succinimidyl carbamate building block coupling on a solid support was done following previously reported procedures.1 All steps were monitored using the chloranil test. 1.5 eq of building block was dissolved in 5 mL of DMF with the addition of 2.5 eq of DIPEA (83 muL, 0.49 mmol). The synthesis was supported by microwave irradiation (60C, 50W, 2 x 15 min). The resin was filtered and washed with DMF (4 × 5 mL). The reduction of azide group was performed with 1M PMe3 solution in THF (10 eq relative to the resin loading) in a mixture of 1,4-dioxane:H2O (5mL, 7:3, v:v) under the microwave irradiation (60C, 50W, 2 x 30 min). After the reaction, the resin was filtered and washed with 1,4-dioxane:H2O (1 × 5 mL) and DMF (4 × 5mL). The resin was then washed trice with DCM, MeOH and Et2O.Final compounds were cleaved from the resin with the use of 5 mL TFA:H2O:TIS (95:2.5:2.5, v:v:v) for 3 h and then precipitated by dropwise addition into a cold diethyl ether. Crude urea-peptide hybrids were collected by centrifugation and purified by preparative RP-HPLC on a C12 column with H2O/ACN gradient containing 0.1% TFA. Peptide fractions were collected, lyophilized and analysed by LC-MS. Molecular weight and elemental composition was confirmed using HRMS. Structural information was obtained using MS/MS. |
Tags: 136552-06-2 synthesis path| 136552-06-2 SDS| 136552-06-2 COA| 136552-06-2 purity| 136552-06-2 application| 136552-06-2 NMR| 136552-06-2 COA| 136552-06-2 structure
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