* 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.
Reference：
[1] Journal of the American Chemical Society, 1977, vol. 99, # 1, p. 235 - 239
2
[ 13734-28-6 ]
[ 692-04-6 ]
[ 1227379-69-2 ]
[ 1227379-72-7 ]
[ 1190-48-3 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 10, p. 6458 - 6464
3
[ 13734-28-6 ]
[ 692-04-6 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 10, p. 6458 - 6464
4
[ 13139-17-8 ]
[ 13734-28-6 ]
[ 2389-45-9 ]
Yield
Reaction Conditions
Operation in experiment
91.9%
With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 30℃; for 16 h;
(2S)-6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoic acid (ii) To a solution of (2S)-6-amino-2-(tert-butoxycarbonylamino)hexanoic acid (100.00 g, 406.01 mmol, 1.00 eq), NaHCO3 (102.33 g, 1.22 mol, 3.00 eq) in THF (1000 mL) and H2O (1000 mL) was added CbzOSu (101.19 g, 406.01 mmol, 1.00 eq) at 0° C. Then the mixture was stirred at 30° C. for 16 hr. The mixture was adjusted to pH=5-6 with 1N HCl, extracted with EA (600 mL*3), dried over Na2SO4, concentrated to give (2S)-6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoic acid (142.00 g, 373.26 mmol, 91.9percent yield) as a yellow oil.
With triethylamine In 1,4-dioxane; water for 18 h; Cooling with ice
[0043] Nα-(tert-butoxycarbonyl)-L-lysine (1) (985 mg, 4 mmol) was dissolved in anhydrous 1,4-dioxane (3 mL) and water (3 mL). After adding triethylamine (615 μL, 4.4 mmol), to the solution was added di-tert-butyl dicarbonate (960 mg, 4.4 mmol) dropwise under ice-cooling, and then the mixture was stirred for 18 hours. Completion of the reaction was confirmed by TLC (ethyl acetate:n-hexane=5:1), and the reaction solution was poured into a 0.5 N aqueous solution of hydrochloric acid (80 mL). The mixture was extracted with ethyl acetate (3×40 mL) and the organic layer was washed with saturated saline (80 mL) and dried over anhydrous magnesium sulfate. After evaporation under a reduced pressure, the obtained material was purified by flash column chromatography (ethyl acetate:n-hexane=1:1 to 2:1) to give intermediate 2 (1.29 g, 93percent) as a white solid. [0044] 1H-NMR (300 MHz, CDCl3) δ: 5.21 (br s, 1H), 4.62 (br s, 1H), 4.28 (br s, 1H), 3.14 (d, 2H, J=6.0 Hz), 1.88 (br s, 1H), 1.76 (br s, 1H), 1.45-1.23 (m, 22H), 0.92-0.88 (m, 1H).
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2112 - 2120
14
[ 56-87-1 ]
[ 24424-99-5 ]
[ 13734-28-6 ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine In water; acetone at 25℃; for 4.5 h;
The L-lysine 10mmol join flask, adding 15 ml, acetone 15 ml, stirring, add 2.08 ml of Et3N, controlling the temperature in the 25 °C under stirring di-tert-butyl dicarbonate to 4.27 ml, and to continue stirring 4.5h, decompression evaporate acetone, the water layer is extracted with ethyl ether 3 times, each 10 ml, with dilute HC1 the aqueous layer to adjust pH value to 2-3 rear, ethyl acetate extraction 3 times, each 15 ml, combined with the organic layer, saturated salt for washing 2 times, each 10 ml, anhydrous Na2SO4after drying, filtration to dryness, the product of the volume ratio obtained for the 1 [...] 2 ethyl acetate mixed solvent to crystallization and petroleum ether, Boc-L-lysine is obtained, the yield is 90percent;
Reference：
[1] Patent: CN102993200, 2016, B, . Location in patent: Paragraph 0050; 0051; 0052
[2] Journal of Materials Chemistry B, 2014, vol. 2, # 42, p. 7351 - 7359
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 1, p. 45 - 47
[4] Chinese Chemical Letters, 2012, vol. 23, # 3, p. 297 - 300
[5] Patent: CN103833623, 2016, B, . Location in patent: Paragraph 0058; 0059; 0062
15
[ 2389-45-9 ]
[ 13734-28-6 ]
Reference：
[1] Synthesis, 1980, vol. NO.11, p. 929 - 932
[2] Tetrahedron Letters, 2002, vol. 43, # 2, p. 311 - 313
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 23, p. 7067 - 7070
[4] Synthetic Communications, 2000, vol. 30, # 14, p. 2525 - 2532
[5] Journal fuer Praktische Chemie (Leipzig), 1969, vol. 311, p. 511 - 519
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1977, p. 490 - 491
[7] Journal of Chemical Research, Miniprint, 1991, # 5, p. 914 - 934
[8] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 10, p. 1077 - 1080
[9] Chemical Communications, 2014, vol. 50, # 86, p. 13085 - 13088
[10] Organic and Biomolecular Chemistry, 2015, vol. 13, # 15, p. 4570 - 4580
[11] Synthesis (Germany), 2017, vol. 49, # 8, p. 1857 - 1866
16
[ 54613-99-9 ]
[ 13734-28-6 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2000, vol. 39, # 7, p. 504 - 508
[2] Tetrahedron Letters, 2002, vol. 43, # 2, p. 311 - 313
[3] Tetrahedron Letters, 2005, vol. 46, # 23, p. 4053 - 4056
17
[ 13734-29-7 ]
[ 13734-28-6 ]
Reference：
[1] Journal of the American Chemical Society, 1986, vol. 108, # 1, p. 140 - 145
18
[ 24424-99-5 ]
[ 13734-28-6 ]
Reference：
[1] Journal of the American Chemical Society, 1986, vol. 108, # 1, p. 140 - 145
[2] Journal of Chemical Research, Miniprint, 1991, # 5, p. 914 - 934
[3] Journal of the American Chemical Society, 2018, vol. 140, # 23, p. 7116 - 7126
With dmap; dicyclohexyl-carbodiimide; at 20℃; for 24h;
Boc-L-lysine (1 eq) was dissolved in isobutanol and dicyclohexylcarbodiimide (DCC) (1.1 eq.) was addedAnd a catalytic amount of 4-dimethylaminopyridine (0.05 equivalents), and the reaction solution was reacted at room temperature for 24 hours.Water and ethyl acetate were added to the reaction solution, followed by extraction. The organic layer was washed with water three times and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a white viscous product.Column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) gave Compound (A).
A solution of Boc-Z-Lys-OH (200 mg, 0.812 mmol) and Boc-Z-Lys(Boc)- OSu (317 mg, 0.834 mmol) in THF-H2O (16.5 mL, 10/1) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The obtained residues were partitioned between water and chloroform. The organic layer EPO <DP n="23"/>was separated and the aqueous layer was extracted with chloroform thrice. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. Purification was accomplished by chromatography on a silica-gel column, eluted with CHCl3/MeOH (40/1, v/v) to afford 369 mg (79%) of product. 1H NMR (500 MHz, CD3OD, 298 K) delta 4.01 (br, 1 H), 3.93 (br, 1 H), 3.20 (m, 2H), 3.02 (t, 3J = 6.78 and 6.91 Hz, 2 H), 1.79-1.30 (m, 39 H).
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 4h;
82%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h;
Boc-Lys[/V-4-Pentynoyl]-OH
Boc-Lys[/V-4-Pentynoyl]-OH: Boc-Lys-OH (1.25 g, 5.1 mmol) was dissolved in anhDMF (15 mL), DIPEA (0.97 mL) was added followed by dropwise addition of a solution of 4-Pentynoic acid succinimidyl ester (5.1 mmol) in anhDMF (8 mL). The reaction mixture was stirred at rt for 3h. The solvent was removed under vacuum. To the crude HCI 1 N (30 mL) was added and extracted with EtOAc (3x40 mL). The combined organic phase was dried over anhNa2S04 and evaporated under vacuum to afford a white solid (1.36g, 82%). MS (ES)" m/z 325 [M-H]", spectroscopic data identical to those reported previously in the literature. [D. P. Nguyen, H. Lusic, H. Neumann, P. B. Kapadnis, A. Deiters and J. W. Chin, J. Am. Chem. Soc. 2009; 131 , 8720-8721.]
82%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 3h;
70%
With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; for 10h;
With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 6.0h;
To a solution of Boc-L-Lysine (0.06 mmol) in 0.4 mL DMF at 0 C., is added triethylamine (0.12 mmol) followed by dropwise addition of DOTA(OtBu)3 NHS ester (0.05 mmol) in 0.5 mL DMF for 10 min with stirring. After 10 min, the ice bath is removed and stirring is continued at room temperature (RT) for 6 h. The reaction mixture is poured over 2 mL ice-cold water and purified by preparative HPLC to obtain DOTA(OtBu)3-Boc-Lys 22.
With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 6.0h;
DOTA(tBu)3-Boc-Lys:10042] To a solution ofN-l3oc-L-Lysine (0.06 mmol) in 0.4 mE DMF at 0 C., is added triethylamine (0.12 mmol) followed by dropwise addition of DOTA(tl3u)3 NHS ester i6 (0.05 mmol) in 0.5 mE DMF for 10mm with stirring. Afier 10 mm, the ice bath is removed and stirring is continued at room temperature (RT) for 6 h. The reaction mixture is poured over 2 mE ice-cold water and purified by preparative HPEC to obtain DOTA(tl3u)3-l3oc-Eys 17.
Stage #1: N-Fmoc L-Phe With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 5h;
Stage #2: With piperidine In N,N-dimethyl acetamide for 0.4h;
Stage #3: c(Trt); C(Trt); L-Norleucine; L-lysine; S(tBu); R(Pbf); acetic anhydride; Boc-Lys-OH; glycine; <i>L</i>-proline Further stages;
12a; 12b; 12c Preparation of Intermediate 1 2a, Preparation of Intermediate 1 2b and Preparation of Intermediate 1 2c
(Loading of 2-Chlorotrityl Chloride Resin with Fmoc-FOH, Fmoc Removal and Determination of the Loading of theResin)2-Chlorotrityl chloride resin (10.0 g, 16.0 mmol) was washed with DCM (3x). A solution of Fmoc-F-OH (12.4 g, 32.0 mmol) in DCM (100 mL) and DIPEA (11.2 mL, 64.0 mmol) was added and the suspension was shaken for 5 h at it. The resin was washed thoroughly with DCMJMeOH/DIPEA (17:2:1) (3x), DCM (3x), DMA (3x), DCM (3x).The resin was then treated twelve times for 2 mm with a mixture ofpiperidine/DMA (1:4) (50 mL each time) followed by washing with DMA (2x). The piperidine/DMA solutionsand DMA washing solutions were collected for determina15 tion of the loading of the resin (see general procedure).The resin was washed thoroughly with DCM (3x), DMA (3x), DCM (3x) and dried in vacuo to give Intermediate 12a (12.8 g; loading=0.79 mmol/g). (Assembly of Linear Peptide)Intermediate 12a (127 mg, 0.10 mmol) was subjected to solid phase peptide synthesis on the PreludeTM peptide synthesizet Coupling was performed as follows: (Cleavage from the Resin with Concomitant ProtectingGroup Removal and Purification)Intermediate 1 2b (0.10 mmol) was carefully washed with DCM (4x). A mixture of 95% aq. TFAEDT/TIS (95:2.5:2.5)(2 mL) was added and the suspension was shaken at it for 2 h.The cleavage solution was filtered off, and fresh cleavagesolution (2 mL) was added. The suspension was shaken at itfor 1 h then the cleavage solution was filtered off. Fresh solution (2 mL) was added and the suspension was shaken at it for 1 h. The cleavage solution was filtered off. The combined cleavage solutions were poured onto a mixture of coldheptane/diethyl ether (1:1) (30 mL), giving a precipitate. Themixture was centrifuged and the supernatant poured off. Thesolid was washed again with cold heptane/diethyl ether (1:1)(10 mL), the mixture was centrifuged and the supernatantpoured off. The solid was dried in vacuo. The crude productwas purified by preparative HPLC and lyophilized to afford Intermediate 12c (53 mg, 0.029 mmol).
Ac-C(Trt)-R(Pbf)-P-R(Pbf)-L-S(tBu)-C(Trt)-K(Boc)-G-P-Nle-P-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37.2 mg
Stage #1: Fmoc-Pro-OH With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h;
Stage #2: With piperidine In N,N-dimethyl acetamide for 0.4h;
Stage #3: C(Trt); L-Norleucine; L-lysine; S(tBu); R(Pbf); acetic anhydride; Boc-Lys-OH; N-Methyl-N-phenethylamine Further stages;
9a; 9b; 9c Preparation of Intermediate 9a
(Loading of 2-Chlorotrityl Chloride Resin with Fmoc-P----OH, Fmoc Removal and Determination of the Loading of the Resin)2-Chlorotrityl chloride resin (2.00 g, 3.20 mmol) was washed with DCM (3x). A solution of Fmoc-P----OH (1.08 g, 3.20 mmol) in DCM (20 mL) and DIPEA (2.24 mL, 12.8 mmol) was added and the suspension was shaken for 3 h at it.The resin was washed thoroughly with DCMJMeOH/DIPEA (17:2:1) (3x), DCM (3x), DMA (3x), DCM (3x).The resin was then treated twelve times for 2 mm with a mixture of piperidine/DMA (1:4) (12 mL each time). Thepiperidine/DMA solutions were collected for determination of the loading of the resin (see general procedure).The resin was washed thoroughly with DCM (3x), DMA (3x), DCM (3x) and dried in vacuo to give Intermediate 9a (2.25 g; loading=1.12 mmol/g). Preparation(Assembly of Linear Peptide)Intermediate 9a (89 mg, 0.10 mmol) was subjected to solidphase peptide synthesis on the PreludeTM peptide synthesizer.Coupling was performed as follows: Preparation of Intermediate 9c(HFIP Cleavage from the Resin)HFIP/DCM (1:3) (3 mL) was added to Intermediate 9b(0.100 mmol) and the suspension was shaken at it for 20 mm.The cleavage solution was filtered off and collected. Thisprocedure was repeated twice. Finally the resin was washedonce with HFIP/DCM (1:3) (1 mL). The combined cleavageand washing solutions were concentrated to dryness in vacuo.The crude product was lyophilized from ACN/H20 to affordIntermediate 9c (37.2 mg, 14.8 jtmol) as a white solid.
TPA-O2Oc-O2Oc-O2Oc-O2Oc-Q-R-P-C-L-S-C-K-G-P-(D-Nle)phenethylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(Assembly of Linear Peptide) 020c-020c-020c-020c- (SEQ ID NO: 62)Phenethylamine-AMEBA resin (Aldrich, 0.25 mmol) issubjected to solid phase peptide synthesis on the Liberty TM microwave peptide synthesizer. Coupling is performed as follows: Preparation of Intermediate lb(Cleavage from the Resin with Concomitant Protecting Group Removal then Purification)A solution made of 1.54 g of DTT and 0.75 mL of thioani-sole in 6 mL of TFATIPS/Water (95:2.5:2.5) is added to Intermediate la (0.25 mmol) and the suspension is shaken at it for 5 hr. The cleavage solution is filtered off and the resin is washed with 95% aq. TFA. The combined cleavage and wash-ing solutions are poured onto cold diethyl ether, giving a precipitate. The suspension is centrifuged andthe supernatant poured off. Diethyl ether is added to the residue, the suspension is vortexed for 3 mm, centrifuged, and the supematant is poured off. The washing process is repeated 3 times. The solidis dried in high vacuum. The crude is purified by preparative HPLC and lyophilized from ACN/H20 to afford Intermediatelb.
Resin)(Loading of 2-Chlorotrityl Chloride Resin with Fmoc-fOH, Fmoc Removal and Determination of the Loading of the2-Chlorotrityl chloride resin (5.0 g, 8.01 mmol) was reacted with a solution of Fmoc-f-OH (3.10 g, 8.01 mmol) in DCM (50 mE) and DIPEA (5.59 mE, 32.0 mmol) in analogy to the general procedure described above to give Intermediate 21a (5.87 g, loading=0.897 mmol/g). (Assembly of Linear Peptide)Intermediate 21a (0.100 mmol) was subjected to solidphase peptide synthesis on the LibertyTM microwave peptide synthesizet Coupling was performed as follows: (Cleavage from the Resin with Concomitant Protecting Group Removal then Purification)A mixture of 95% aq. TFAEDT/DTT (95:2.5:2.5) (2 mE)was added to Intermediate 21b (0.1 mmol). The suspensionwas shaken at it for 2 h, then the cleavage solution was filtered off. The resin was then again treated with 95% aq. TFAEDT/ TIS (95:2.5:2.5) (2 mE), shaked at it for 1 h, and filtered. The combined cleavage and washing solutions were poured ontoa mixture of cold heptane/diethyl ether (1:1) (11 mL), giving a precipitate. The suspension was centriffiged and the supernatant poured off. Diethyl ether (10 mL) was added to the residue, the suspension was vortexed for 3 mm and centrifuged, and the supernatant was poured off. The washing pro-cess was repeated twice. The solid was dried in high vacuum The crude was purified by preparative HPLC and lyophilized from ACN/H20 to afford Intermediate 21c (55 mg, 0.030 mmol).
(9H-fluoren-9-yl)methyl pyrrolidin-1-yl carbonate[ No CAS ]
[ 84624-27-1 ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane; water; at 20℃; for 24h;Cooling with ice;
To a cold (ice bath) solution of (S)-6-amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (8.5 g) in a mixture of 5% aqueous NaHCC>3 solution (300 inL) and 1,4-dioxane (40 mL) was added dropwise a solution of (9H-fluoren-9-yl)methyl pyrrolidin-l-yl carbonate (11.7 g) in 1,4-dioxane (40 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. Three additional vials were set up as described above. After the reactions were complete, the four reaction mixtures were combined, and the organic solvent was removed under vacuum. The aqueous layer was acidified to pH 3 with aqueous hydrochloric acid solution (IN) and then extracted with ethyl acetate (3 chi 500 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to give a crude compound, which was recrystallized from methyl tert-butyl ether to afford the title compound. NMR (400MHz, chloroform- ) delta 11.05 (br. s., 1H), 7.76 (d, 2H), 7.59 (d, 2H), 7.45 - 7.27 (m, 4H), 6.52 - 6.17 (m, 1H), 5.16 - 4.87 (m, 1H), 4.54 - 4.17 (m, 4H), 3.26 - 2.98 (m, 2H), 1.76 - 1.64 (m, 1H), 1.62 - 1.31 (m, 14H).
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 24h;Cooling with ice;
1.66.1 (S)-6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-((tert- butoxycarbonyl)amino)hexanoic acid [000755] To a solution of (S)-6-amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (8.5 g) in a mixture of 5% aqueous NaHC03 solution (300 mL) and dioxane (40 mL), chilled in an ice bath, was added dropwise a solution of (9H-fluoren-9-yl)methyl pyrrolidin-l-yl carbonate (11.7 g) in dioxane (40 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. Three additional vials were set up as described above. After the reaction was completed, all four reaction mixtures were combined, and the organic solvent was removed under vacuum. The aqueous residue was acidified to pH 3 with aqueous hydrochloric acid solution (IN) and then extracted with ethyl acetate (3 chi 500 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to give a crude compound which was recrystallized from methyl tert-butyl ether to afford the title compound. NMR (400MHz, chloroform- ) delta 11.05 (br. s., 1H), 7.76 (d, 2H), 7.59 (d, 2H), 7.45 - 7.27 (m, 4H), 6.52 - 6.17 (m, 1H), 5.16 - 4.87 (m, 1H), 4.54 - 4.17 (m, 4H), 3.26 - 2.98 (m, 2H), 1.76 - 1.64 (m, 1H), 1.62 - 1.31 (m, 14H).
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 24h;Cooling with ice;
To a solution of (S)-6-amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (8.5 g) in a mixture of 5% aqueous NaHCO3 solution (300 mL) and dioxane (40 mL), chilled in an ice bath, was added dropwise a solution of (9H-fluoren-9-yl)methyl pyrrolidin-1-yl carbonate (11.7 g) in dioxane (40 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. Three additional vials were set up as described above. After the reaction was completed, all four reaction mixtures were combined, and the organic solvent was removed under vacuum. The aqueous residue was acidified to pH 3 with aqueous hydrochloric acid solution (1N) and then extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to give a crude compound which was recrystallized from methyl tert-butyl ether to afford the title compound. 1H NMR (400MHz, chloroform-d) delta ppm 11.05 (br. s., 1H), 7.76 (d, 2H), 7.59 (d, 2H), 7.45 - 7.27 (m, 4H), 6.52 - 6.17 (m, 1H), 5.16 - 4.87 (m, 1H), 4.54 - 4.17 (m, 4H), 3.26 - 2.98 (m, 2H), 1.76 - 1.64 (m, 1H), 1.62 - 1.31 (m, 14H).
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 24h;Cooling with ice;
To a solution of (S)-6-amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (8.5 g) in amixture of 5% aqueous NaHC03 solution (300 mL) and dioxane (40 mL), chilled in an ice bath, wasadded dropwise a solution of (9H-fluoren-9-yl)methyl pyrrolidin-1-yl carbonate (11.7 g) in dioxane(40 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 2435 hours. Three additional vials were set up as described above. After the reaction was completed, allfour reaction mixtures were combined, and the organic solvent was removed under vacuum. The aqueous residue was acidified to pH 3 with aqueous hydrochloric acid solution (IN) and thenextracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine,dried over magnesium sulfate, filtered, and concentrated under vacuum to give a crude compoundwhich was recrystallized from methyl tert-butyl ether to afford the title compound. 1H NMR5 ( 400MHz, chloroform-d) 8 I1.05 (br. s., IH), 7.76 (d, 2H), 7.59 (d, 2H), 7.45 - 7.27 (m, 4H), 6.52-6.17 (m, IH), 5.I6- 4.87 (m, IH), 4.54-4.17 (m, 4H), 3.26-2.98 (m, 2H), 1.76- 1.64 (m, IH), 1.62-1.3I (m, I4H).
With sodium hydrogencarbonate; In 1,4-dioxane; at 20℃; for 24h;Cooling with ice;
To a cold (ice bath) solution of (S)-6-arnino-2-((tert-butoxycarbonyl)arnino)hexanoic acid (8.5 g) in amixture of 5% aqueous NaHCO3 solution (300 mL) and 1,4-dioxane (40 mL) was added dropwise asolution of (9H-fluoren-9-yl)methyl pyrrolidin-1 -yl carbonate (11.7 g) in 1 ,4-dioxane (40 mL). The reaction mixture was allowed to warm to room temperature and was stined for 24 hours. Three additional vials were set up as described above. After the reactions were complete, the four reaction mixtures were combined, and the organic solvent was removed under vacuum. The aqueous layerwas acidified to pH 3 with aqueous hydrochloric acid solution (1 N) and then extracted with ethyl acetate (3 x 500 ntL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to give a crude compound, which was recrystallized from methyl tert-butyl ether to afford the title compound. 1H NMR (400MHz, chloroform-d)ppm 11.05 (hr. s., 1H), 7.76 (d, 2H), 7.59 (d, 2H), 7.45 -7.27 (m, 4H), 6.52- 6.17 (m, 1H), 5.16 -4.87 (m, 1H), 4.54 - 4.17 (m, 4H), 3.26 - 2.98 (m, 2H), 1.76 - 1.64 (m, 1H), 1.62 - 1.31 (m, 14H).
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 24h;Cooling with ice;
To a solution of (S)-6-amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (8.5 g) in a mixture of 5% aqueous NaHCO3 solution (300 mL) and dioxane (40 mL), chilled in an ice bath, was added dropwise a solution of (9H-fluoren-9-yl)methyl pyrrolidin-1-yl carbonate (11.7 g) in dioxane (40 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. Three additional vials were set up as described above. After the reaction was completed, all four reaction mixtures were combined, and the organic solvent was removed under vacuum. The aqueous residue was acidified to pH 3 with aqueous hydrochloric acid solution (1N) and then extracted with ethyl acetate (3*500 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to give a crude compound which was recrystallized from methyl tert-butyl ether to afford the title compound. 1H NMR (400 MHz, chloroform-d) delta 11.05 (br. s., 1H), 7.76 (d, 2H), 7.59 (d, 2H), 7.45-7.27 (m, 4H), 6.52-6.17 (m, 1H), 5.16-4.87 (m, 1H), 4.54-4.17 (m, 4H), 3.26-2.98 (m, 2H), 1.76-1.64 (m, 1H), 1.62-1.31 (m, 14H).
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 24h;Cooling with ice;
To a cold (ice bath) solution of (S)-6-amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (8.5 g) in a mixture of 5% aqueous NaHCO3 solution (300 mL) and 1,4-dioxane (40 mL) was added dropwise a solution of (9H-fluoren-9-yl)methyl pyrrolidin-1-yl carbonate (11.7 g) in 1,4-dioxane (40 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. Three additional vials were set up as described above. After the reactions were complete, the four reaction mixtures were combined, and the organic solvent was removed under vacuum. The aqueous layer was acidified to pH 3 with aqueous hydrochloric acid solution (1N) and then extracted with ethyl acetate (3*500 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to give a crude compound, which was recrystallized from methyl tert-butyl ether to afford the title compound. 1H NMR (400 MHz, chloroform-d) delta 11.05 (br. s., 1H), 7.76 (d, 2H), 7.59 (d, 2H), 7.45-7.27 (m, 4H), 6.52-6.17 (m, 1H), 5.16-4.87 (m, 1H), 4.54-4.17 (m, 4H), 3.26-2.98 (m, 2H), 1.76-1.64 (m, 1H), 1.62-1.31 (m, 14H).
2-((1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)hexadecanoic acid[ No CAS ]
Ac-KLIPNASLIENCTKAELK(Ac-KQAEDKVKASREAKKQVEKALEQLEDKVK)-SS-(2-amino-D,L-hexadecanoyl)-2-amino-D,L-hexadecanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12.5%
General procedure: LCP 1 was synthesised by coupling Dde-C16 onto pMBHA resin(0.45 mmol/g; 0.2 mmol scale) by using HBTU (4.0 equiv) andDIPEA (6.2 equiv) in DMF (2 1 h). Removal of the Dde-protectinggroup was performed by treatments with 2% hydrazine in DMF(2 30 min). The remaining LCP sequence was synthesised bymicrowave-assisted Boc-SPPS. Amino acid activation was achievedby dissolving Boc-amino acids (4.2 equiv) in 0.5 M HBTU(4.0 equiv) in DMF, followed by the addition of DIPEA (6.2 equiv).The amino acid coupling cycle consisted of Boc-deprotection withneat TFA at room temperature (2 1 min), 2 min DMF flow wash,followed by 10 min coupling with the pre-activated amino acid.The temperature was set at 70 C (35 W, 10 min) for all aminoacids, except for Cys and His, which were coupled at 50 C (35 W,10 min). N-terminal acetylation and final cleavage from resin wasperformed as reported previously.29 The lyophilised products werepurified by RP-HPLC. The collected fractions were analysed byESI-MS and RP-HPLC. Where appropriate, fractions were combinedand lyophilised to yield pure product.For the synthesis of LCP 2, Dde-C20 was coupled onto pMBHAresin (0.45 mmol/g; 0.2 mmol scale). The remaining proceduresfollowed that of the synthesis of LCP 1, as mentioned above.LCP 1 yield: 12.5%. Purity: 90%. Molecular weight: 6086.4. ESIMS:[M+4H]4+ m/z 1523.4 (calcd: 1522.6), [M+5H]5+ m/z 1218.4(calcd: 1218.3), [M+6H]6+ m/z 1015.7 (calcd: 1015.3), [M+7H]7+m/z 870.6 (calcd: 870.4), [M+9H]9+ m/z 677.5 (calcd: 677.3), [M+10H]10+ m/z 608.8 (calcd: 609.5). Rt = 25.0 min (0-100% solventB, 40 min, C4-column).
Ac-KLIPNASLIENCTKAELK(Ac-KQAEDKVKASREAKKQVEKALEQLEDKVK)-SS-(2-amino-D,L-eicosanoyl)-2-amino-D,L-eicosanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18.5%
General procedure: LCP 1 was synthesised by coupling Dde-C16 onto pMBHA resin(0.45 mmol/g; 0.2 mmol scale) by using HBTU (4.0 equiv) andDIPEA (6.2 equiv) in DMF (2 1 h). Removal of the Dde-protectinggroup was performed by treatments with 2% hydrazine in DMF(2 30 min). The remaining LCP sequence was synthesised bymicrowave-assisted Boc-SPPS. Amino acid activation was achievedby dissolving Boc-amino acids (4.2 equiv) in 0.5 M HBTU(4.0 equiv) in DMF, followed by the addition of DIPEA (6.2 equiv).The amino acid coupling cycle consisted of Boc-deprotection withneat TFA at room temperature (2 1 min), 2 min DMF flow wash,followed by 10 min coupling with the pre-activated amino acid.The temperature was set at 70 C (35 W, 10 min) for all aminoacids, except for Cys and His, which were coupled at 50 C (35 W,10 min). N-terminal acetylation and final cleavage from resin wasperformed as reported previously.29 The lyophilised products werepurified by RP-HPLC. The collected fractions were analysed byESI-MS and RP-HPLC. Where appropriate, fractions were combinedand lyophilised to yield pure product.For the synthesis of LCP 2, Dde-C20 was coupled onto pMBHAresin (0.45 mmol/g; 0.2 mmol scale). The remaining proceduresfollowed that of the synthesis of LCP 1, as mentioned above.LCP 1 yield: 12.5%. Purity: 90%. Molecular weight: 6086.4. ESIMS:[M+4H]4+ m/z 1523.4 (calcd: 1522.6), [M+5H]5+ m/z 1218.4(calcd: 1218.3), [M+6H]6+ m/z 1015.7 (calcd: 1015.3), [M+7H]7+m/z 870.6 (calcd: 870.4), [M+9H]9+ m/z 677.5 (calcd: 677.3), [M+10H]10+ m/z 608.8 (calcd: 609.5). Rt = 25.0 min (0-100% solventB, 40 min, C4-column).
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;
The 2.6mmol of the of L-threonine and 1.3mmol <strong>[144598-75-4]paliperidone</strong> dissolved in 7.5 ml of anhydrous dichloromethane, catalyst 4-dimethyl aminopyridine and N, N '-dicyclohexyl carbodiimide to anhydrous dichloromethane to dissolve in the 0 C add 10mmol, under conditions such that the stirring 3-5h, stirring at room temperature 48h, the <strong>[144598-75-4]paliperidone</strong> 9 hydroxyl and amino acid carboxyl to undergo esterification reaction, is filtered to remove the filter residue, the filtrate plus dichloromethane to 30 ml, using 5% sodium carbonate solution to washing 3 times, each 10 ml, water for 3×10 ml wash to neutral; drying by anhydrous sodium sulfate, filtered, filtrate evaporate most of the solvent, neutral oxidation column purification, wet france installs the column, dry sample, then with ethyl acetate: ethanol = 90 the [...] 1 elution agent flushing, to obtain the product, turns on lathe does solution, then with a small amount of anhydrous dichloromethane soluble, EP tube into the dry, and then to full evaporation to dryness in a round-bottom flask, to yield 65%
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
(S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-ureidopentanoic acid[ No CAS ]
[ 203854-51-7 ]
C41H76N10O13[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
(S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-ureidopentanoic acid[ No CAS ]
C40H74N10O12[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
(S)-2-N-(9-fluorenylmethoxycarbonyl)-amino-6-trimethylammonium hexanoic acid[ No CAS ]
[ 35661-60-0 ]
[ 35737-10-1 ]
[ 13734-28-6 ]
[ 91000-69-0 ]
[ 144120-53-6 ]
C43H82N11O11(1+)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4,4-dimethylpentanoic acid[ No CAS ]
C41H77N11O11[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
General procedure: Solid phase peptide synthesis (0.2 mmol scale) was performed on aminomethyl PS resin (1.0 mmol/g) based on the Fmoc based strategy. HMPB linker was attached to the resin using general method A, and coupling of the first amino acid residue to theHMPB-PS resin was performed according to general method B or C. The degree of attachment of the first amino acid residue to the resin was determined using UV spectrophotometry.16 The desired peptide sequences were synthesised using general method D onTributeTM peptide synthesiser, and peptide coupling of unnatural amino acids was performed manually according to general method E. The linear peptides were cleaved from the resin using general method F, and the crude products were cyclised using general method G. The side-chain protecting groups were removed from the cyclised peptides according to general method H, and the allyl protecting group was removed according to general method I. The crude peptides were purified according to general method J
Stage #1: 2-Chloro-4,6-diamino-1,3,5-triazine; Boc-Lys-OH With sodium hydroxide In water at 85℃;
Stage #2: With trifluoroacetic acid for 2h;
3.3. Synthesis of the Lysine Derivative of Melamine
Boc-Lys-OH (4.94 g, 20 mmol) was stirred with 6-chloro-2,4-diamino-1,3,5-triazine (3.49 g,24 mmol) and NaOH (1.60 g, 40 mmol) in 35 mL of water at 85 C overnight. Solid was removed fromthe solution by centrifuge and the solution was extracted with EtOAc six times. The aqueous solutionwas then dried under reduced pressure. The Boc protecting group was then removed in 15 mL TFA for2 h. Most TFA was removed under reduced pressure and to the resulting sticky oil was added colddiethyl ether to precipitate the product. M-Lys was further purified by washing with EtOH. 1H NMR(400 MHz, 90% d6-DMSO + 10% Trifluoroacetic acid-d): (ppm) 1.29-1.54 (m, 4H), 1.80 (q, J = 8.0 Hz,2H), 3.26 (t, J = 8.0 Hz, 2H), 3.89 (t, J = 8.0 Hz, 1H), 7.79-8.71 (m, 2H, acidic protons are suppressedin this acidic NMR solvent and cannot accurately reflect the number of protons). Calculated [M + H]256.1524; Found [M + H]: 256.1680.
Stage #1: Fmoc-Gly-Wang resin With piperidine In N,N-dimethyl-formamide for 0.0666667h;
Stage #2: 3-(tritylthio) propanoic acid With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In N,N-dimethyl-formamide for 16h;
Stage #3: N-(tert-butyloxycarbonyl)-L-isoleucine; <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-leucine; L-N-Boc-Ala; Boc-Glu; Boc-Lys-OH Further stages;
4.3. Manual solid phase synthesis of peptide thioester 2
To 21.7 mg (10 mmol) of Fmoc-glycine loaded MBHA-resin(0.46 mmol g1) in a 3 ml syringe reactor was added DMF. For Fmoc cleavage a solution of piperidine/DMF (1:4) was added. After 2 min the solvent was removed by filtration and the procedure was repeated once. A solution of 10 eq 3-trityl-mercaptopropionic acid,10 eq. PyBOP, and 12 eq. NMM in DMF (350 ml) was added to the washed resin. The solution was removed by filtration after 16 h. The resin was washed (3 DMF, 3 CH2Cl2, 3 DMF). For capping,1 ml pyridine/Ac2O (9:1) was added to the resin. After5 min the resin was washed (3 DMF, 3 CH2Cl2, 3 DMF). The trityl group was cleaved by treating the resin with 5% TIS in TFA for 30 min. The resin was washed with dichloromethane (10) followedby DMF (5). For coupling of C-terminal and subsequent amino acids 4 eq. Boc-AA-OH, 3.6 eq. HCTU and 8 eq. NMM were dissolved in 500 ml DMF. The solution was added to the resin.The resin was washed (3 DMF, 3 CH2Cl2, 3 DMF) after 30 min. Uncoupled amino groups were capped with pyridine/Ac2O (9:1). The Boc-protection group was cleaved by treating theresin with a solution of TFA/m-cresol (95:5) for 5 min. Prior to the final cleavage the resin was washed with dichloromethane and dried under reduced pressure. The dried resin was treated with a solution (1.5 ml per 10 mmol) of TFA/TFMSA/m-cresol (80:15:5)for 90 min. The cleavage solution was filtered and added to dryice cooled diethyl ether. The peptide precipitate was collected byfiltration (4000 rpm, 20 min, 4 C). The residue was dissolved in H2O/acetonitrile/TFA (1/1/0.001) and aliquots of 3 mmol were purified by preparative HPLC: Yield: 2.01 mmol (67%).UPLC: tR = 1.25 min (3% B?90% B in 2 min). MALDI-TOF-MS:m/z = 2041.60 (C93H171N24O24S [M+H]+, calculated: 2041.57).
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 3h;
To a solution of (2S)-6-amino-2-(tert-butoxycarbonylamino)hexanoic acid (1 g, 4.06 mmol) in THF (10.0 mL) was added a solution of NaHCC>3 (682.14 mg, 8.12 mmol) in water (10.0 ml_) and FmocOSu (1 .51 g, 4.47 mmol). The reaction mixture was stirred at 20 C for 3 hrs. The reaction mixture was poured into water (10.0 mL). The solution was adjusted to pH4 with saturated citric acid solution. The mixture was extracted with EtOAc (15 mL*3). The combined organic extracts were washed with brine (20.0 mL), dried over Na2SC>4 and filtered. The filtrate was concentrated to give intermediate i-53a as a white solid. The compound was used directly in the next step. LCMS (ESI) m/z: [M+Na]+ = 491 .4
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 23℃; for 2h;
To 2,5-dioxopyrrolidin-l-yl 2-(tert- butoxycarbonylaminooxy) acetate (399 mg, 1,384 mmol) and Boc-Lys-OH (335 mg, 1.360 mmol) in DMF (5 mL), was added DIEA (750 ul, 4.306 mmol) at 23 C. After 2h, the solvent was removed in vacuo. The residue was dissolved in EtOAc (50 ml) and washed with IN HC1 (50 ml) and brine (20 mL). The organic layer was dried over MgSCL, filtered, and the solvent removed in vacuo. The residue was purified by flash chromatography to obtain compound 215 (480 mg, 1.144 mmol, 83%) as a white solid. MS m/z 420 (M+H)+.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
