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CAS No. : | 68528-80-3 | MDL No. : | MFCD00049059 |
Formula : | C16H20N2O8 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZWIBGKZDAWNIFC-UHFFFAOYSA-N |
M.W : | 368.34 | Pubchem ID : | 100658 |
Synonyms : |
DSS Crosslinker;Disuccinimidyl Suberate;NSC 340008;DSS
|
Num. heavy atoms : | 26 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.62 |
Num. rotatable bonds : | 11 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 91.79 |
TPSA : | 127.36 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.62 cm/s |
Log Po/w (iLOGP) : | 2.35 |
Log Po/w (XLOGP3) : | -0.1 |
Log Po/w (WLOGP) : | -0.22 |
Log Po/w (MLOGP) : | 0.89 |
Log Po/w (SILICOS-IT) : | 0.98 |
Consensus Log Po/w : | 0.78 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.33 |
Solubility : | 17.0 mg/ml ; 0.0463 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.12 |
Solubility : | 2.78 mg/ml ; 0.00755 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.08 |
Solubility : | 3.06 mg/ml ; 0.0083 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.05 |
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 |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h; | Organic synthesisGeneral procedure for the synthesis of linker molecules (compound 1 and 2)To a solution of the di-acid (suberic acid or 3,3?-dithiodipropionic acid) (500 mg, 2.4 mmol) indry DCM (10 mL)was added EDC?HCI (1.37 g, 7.1 mmol) and N-hydroxysuccinimide (656.8mg, 5.7 mmol). The mixture was stirred for 2 hours at rt. The organic phase was washed witha 2.5% aqueous solution of NaHSO4 (2 x 10 mL) and brine (10 mL), dried over anhydrous Na2504, filtered and concentrated in vacuo. No further purification was performed. Both compounds 1 and 2 were isolated as white solids with full conversion. DSS linker (Disuccinimidyl suberate) (compound 1) 1H NMR (400 MHz, CDCI3) 62.82 (s, 8H), 2.60 (dt, J = 2.5, 7.4 Hz, 4H), 1.80-i .71 (m, 4H),1.48-1.42 (m, 4H). 13C NMR (100 MHz, CDCI3) 6 169.3, 168.6, 30.9, 28.2, 25.7, 24.4. | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetone; at 25℃; for 24h; | General procedure: NHS-Cn was prepared as described by Chen et al. (2011) with a small modification; end-bit binary acid (15 mmol each; C2, C3, C4, C5, C6, C8, C10, C14) and NHS (40 mmol) were dissolved in acetone (25 mL), and then EDC (30 mmol) was added to the solution. The clear mixture was gently stirred at 25C for 24 h. After the acetone was removed by rotary evaporation under reduced pressure, the residue was washed several times with deionised water and then dried under vacuum at 50C. The crosslinker thus prepared was characterised by the 1H NMR and FT-IR spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | In DMF (N,N-dimethyl-formamide); water; for 24h;pH 7.4;phosphate buffer; | <strong>[68528-80-3]disuccinimidyl suberate</strong> (Pierce #21555) (5.86 mg) was mixed with FFR-CMK (25 mg) in 1.5 ml of phosphate buffer PH 7.4, after addition of two drops of DMF the mixture was stirred in a closed vessel under N2 atmosphere for 1 day, subsequent evaporation yielded an yellow oil raw product (35 mg) which was purified on HPLC (reversed-phase column (Symmetry Shield,C8, Waters, Part no. WAT200655)) with a constant flow of 1 ml/min.Elution was accomplished by increasing the percentage of organic phase (acetonitrile contaning 0.1% trifluoroacetic acid (TFA)) relative to aqueous phase (0.1% TFA in H2O).A linear gradient from 14% to 50% organic phase over 35 min was used where the dimeric form of FFR-CMK was eluted at about 28 min.) The fraction at rt (retention time) 30.94 min was isolated. MS (M+1) 1141 yield 12% oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N-methyl-acetamide; ethanol; water; N,N-dimethyl-formamide; | EXAMPLE 1 Synthesis of biotinoyl-amino-3,6-dioxaoctanylamino-carbonyl-heptanoic acid-N-hydroxysuccinimide ester (biotin-DADOO-DSS or biotin-DDS) A solution of 561 mg (1.5 mmol) biotinoyl-1,8-diamino-3,6-dioxaoctane (biotin-DADOO, Boehringer Mannheim, Catalogue No. 1112074) in 25 ml freshly distilled dimethylformamide (DMF) is admixed with 0.21 ml (1.5 mmol) triethylamine and slowly added dropwise while stirring to a solution of 5.52 g (15 mmol) <strong>[68528-80-3]disuccinimidyl suberate</strong> (DSS, Boehringer Mannheim, Catalogue No. 1081730) in 50 ml freshly distilled DMF. It is allowed to stir for 18 hours at room temperature. Afterwards the solution is evaporated on a rotary evaporator in an oil pump vacuum, the semi-solid residue is digested with ca. 70 ml water and the excess DSS is separated by filtration. The clear solution is lyophilized and the lyophilisate is subsequently digested with a small amount of THF. After suction filtering the solid product it is dried in a high vacuum. Yield: 620 mg colourless powder. TLC: Silica gel 60 (Merck); ethyl acetate/glacial acetic acid/water 6/3/1 (v/v/v); spraying with a mixture of 1/1 (v/v) of A) 2% H2 SO4 in ethanol and B) 0.2% 4-dimethylamino-cinnamaldehyde in ethanol and subsequently drying for 10 minutes at 100 C. yields a raspberry-red spot of the product at Rf =0.51. 1 H-NMR(d6 -DMSO): delta=1.10-1.80 (m, 14 H), 2.05 (t, 4H), 2.65 (t, 2H), 2.80 (s, 4H), 2.60-3.60 (m, 11H), 3.50 (s, 4H), 4.05-4.40 (m,2 H), 6.36 (d, br, 2H), 7.80 (t, br, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Example 5The following example illustrates the preparation of a compound of Formula II comprising an activated N-hydroxysuccinimide ester (7-(2-[2-(6-Methoxy-1,3-dioxo-1H,3H-dibenzo[de,h]isoquinolin-2-yl)-ethyl]-methyl-amino}-ethylcarbamoyl )-heptanoic acid 2,5-dioxo-pyrrolidin-1-yl ester) (MD167).0.130 mmol of 2-{2-[(2-aminoethyl)methylamino]ethyl}-6-methoxy-1,2-dihydro-3H-dibenzo[de,h]isoquinoline-1,3-dione (MD117; Example 1, Step G)×2HCl in anhydrous DMF (1 ml) was added by slowly dropping over 30 minutes to a stirred mixture of 0.260 mmol (95.6 mg) DSS (octanedioic acid di-N-hydroxysuccinimide ester; PIERCE biotechnology) and 0.389 mmol (69 mul) DIEA in 5 ml of anhydrous DMF. The reaction mixture was stirred for an additional two and one-half hours, then solvent was evaporated. The formation of the dimer (MD168) as a major byproduct was observed. The crude product was purified by HPLC using a reverse phase C18 column and a water/acetonitrile solvent system with 0.1% of TFA as ion pairing reagent. Total MD167×TFA yield after purification was 56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl) 3-(6,8-dichloro-2-methyl-l,2,3,4 tetrahydroisoqumolin-4 yl)benzenesulfonamide (compound 28) (54 5mg, 0 lmmol) in DMF (0 2OmL) was added DIEA (15 5mg, 0 12mmol) and bis(2,5 dioxopyrrolidm-1- yl) octanedioate (18 4mg, 0 05mmol) The reaction was stirred at room temperature for 3 hours at which point an additional 0 03mmol of compound 28 was added After a further hour the solvent was removed and the resulting residue dissolved in acetomt?le/water (1 1) and pu?fied by preparative HPLC to give the title compound (17 4mg) as a TFA salt 1H-NMR (400MHz, CD3OD) 7 89 (d, 2H), 7 78 (s, 2H), 7 64 (t, 2H), 7 52 (m, 4H), 6 83 (s, 2H), 4 81 (m, 4H), 4 45 (d, 2H), 3 89 (dd, 2H), 3 61 (m, 18H), 3 55 (m, 10H), 3 47 (m, 5H), 3 33 (m, 5H), 3 14 (s, 7H), 3 04 (t, 4H), 2 16 (t, 4H), 1 55 (m, 4H), 1 29 (m, 4H) MS (m/z) 1231 87 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In N,N-dimethyl-formamide; for 2h; | asolution containing (S) - di -tert- butyl 2- (3 - ((S) -6- amino -1-tert-butoxy-1-oxo-hexane-2-yl) ureido) pentanedionate ( 0.488 g, 1.0mmol) in DMF(20mL) was added drop-by-drop via a syringe pump to a solution containingsuberic acid bis (N-hydroxysuccinimide ester) (1.47g, 4.0 mmol) in DMF (80mL).After 2 hours, the solvent was evaporated under reduced pressure to generate aresidue, which was purified by flash chromatography on silica gel eluting withAcCn / DCM to produce (S) - di-tert- butyl 2- (3 - ((S ) -1-tert- butoxy-6- (8-(2,5-dioxopyrrolidin-1-yloxy) -8-oxo-octane amide) -1-oxo-hexane-2-yl) ureido)pentanedionate (0 .54g, 73%). |
73% | In N,N-dimethyl-formamide; at 2℃;Inert atmosphere; | A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (0.488 g, 1.0 mmol) in DMF (20 mL) was added dropwise to a solution of <strong>[68528-80-3]suberic acid bis(N-hydroxysuccinimide ester)</strong> (1.47 g, 4.0 mmol) in DMF (80 mL) via a syringe pump. After 2 h, the solvent was evaporated under reduced pressure to give a residue, which was purified by flash chromatography over silica gel eluting with AcCN/DCM to give (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.54 g, 73%). MS (ESI), 741.6 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; for 0.25h; | Synthesis of L6 (Ex. 90) To a solution of 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5- ureidopentanamido)benzyl (2-(pyridin-2-yldisulfanyl)ethyl)carbamate L4 (238 mg, 0.346 mmol) in dimethylsulfoxide (1.5 mL) was added a solution of bis(2,5-dioxopyrrolidin-l-yl) octanedioate L5 (509 mg, 1.382 mmol) and triethylamine (0.096 mL, 0.691 mmol). The reaction mixture was aged for 15 min and purified on a silica gel column (80g) using a gradient of 1-10% methanol/dichloromethane over 30 min at 60 mL/min to give L6 as a solid. MS(m/z): 845 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; N,N-dimethyl-formamide; acetonitrile; | 2-{3-[5-[7-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-heptanoylamino]-1-(4-methoxy-benzyloxycarbonyl)-pentyl]-ureido}-pentanedioic acid bis-(4-methoxy-benzyl) ester (6) A 100 mL round bottom flask was flame dried under N2, after which 1 (0.08 g, 0.12 mmol) was added and then dissolved in 10 mL of dry DMF. This solution was added dropwise to a solution of <strong>[68528-80-3]suberic acid bis-(N-hydroxysuccinimide ester)</strong>, DSS, (0.13 g, 0.35 mmol in 10 mL DMF) at room temperature with mild stirring. After 2 h, the volume of the solution was reduced under vacuum and the colorless solid residue was kept under high vacuum for 2 h further to remove traces of DMF. The residue was dissolved in 1 mL of CH2Cl2 and was loaded onto silica gel column (1 inch*12 inch). Initially the column was eluted with 40/60 CH3CN/CH2Cl2 to remove excess DSS followed by 50/50 CH3CN/CH2Cl2 to afford the product as a colorless solid. Yield: 0.062 mg, 0.07 mmol, 56.6%. TLC Rf=0.47 (5/95 MeOH/CH2Cl2) 1H NMR (CDCl3) delta: 7.26 (m, 6H), 6.86 (m, 6H), 5.91 (m, 1H), 5.37 (m, 4H), 5.03 (m, 6H), 4.43 (m, 3H), 3.79 (s, 9H), 3.31 (m, 4H), 2.82 (s, 4H), 2.58 (t, J=8.4 Hz, 2H), 2.37 (m, 2H), 2.14 (m, 4H), 1.71-1.21 (m, 9H). ESIMS na/z: 933 [M+1], (HRFAB+-MS): Cacld for C48H61N4O15 [M+1]+, 933.4133, found 933.4142 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In N,N-dimethyl-formamide; at 0℃; for 0.5h; | To a finely ground mixture of <strong>[68528-80-3]suberic acid bis(N-hydroxysuccinimide ester)</strong> (37 mg, 0.1 mmol) in DMF (1.5 ml) at 0, 5.5 mul of O,O-(dipropylamine diethyleneglycol) was added by dropwise and stirred for 30 min and fractionated by RP-HPLC to give product 1 (10.3 mg, 57% yield), using initial isocratic eluting with acetonitrile: TFA (v/v = 250:1) in water, followed by gradient eluting from acetonitrile: TFA (v/v = 250:1) in water to acetonitrile (100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With pyridine; at 20℃; for 3h; | All Val-Cit-PAB-MMAF prepared from 67 mg of Fmoc-Val-Cit-PAB-MMAF, was suspended in pyridine (2 mL),and added to a solution of <strong>[68528-80-3]disuccinimidyl suberate</strong> (74 mg, 0.2 mmol, 4 eq.), in pyridine (1 mL). Reaction mixture wasstirred at room temperature. After 3 hrs ether (20 mL) was added. Precipitate was collected, washed with additionalamount of ether. Reddish solid was suspended in 30% MeOH/CH2Cl2, filtered trough a pad of silica gel with 30%MeOH/CH2Cl2 as an eluent. Compound 17 was obtained as white solid, 20 mg (29% yield). ES-MS m/z 1388.5 [M-H]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
After these couplings, the resin was removed from the Liberty synthesizer and was washed, drained, and treated with 5 ml hexafluoro isopropanol for 10 minutes. The resin was then washed with DCM and drained. Then, the hexafluoro isopropanol treatment and DCM washing was repeated. (0154) Suberic acid bis-NHS ester (368 mg) was dissolved in NMP (10 ml, with 0.5 mM bromophenol blue) and DIPEA (170 mul) was added. This solution was added to the drained resin and allowed to react overnight. After the coupling, the resin was washed with NMP, DCM and drained. To the drained resin, a mixture of TFA:TIPS:mercaptoethanol:H2O 94:1:2.5:2.5 was added and the resin was shaken at ambient temperature for 2 hours. The resin was drained slowly into 75 ml ice-cooled diethyl ether resulting in precipitation of the product. Further stirring at rt. for 0.5 hour and centrifugation yielded the product as a solid which was washed twice with diethylether and dried in vacuo. The crude product was dissolved in a mixture of acetonitrile containing HPLC A- and B-buffers, and purified by preparative RP-HPLC using a gradient of acetonitrile/water buffers with 0.1% TFA. Product identity and purity was confirmed by HPLC and LCMS. Using the above protocol, a highly complex albumin binding side chain was prepared as an NHS ester. This compound is set up to react with GSC in example 17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.4% | With triethylamine; In N,N-dimethyl-formamide; for 1h;Inert atmosphere; | Europium complex 2-8.Eu (11.9 mg, 11.6 tmol) was partially dissolved in dimethylformamide (400 tL) and triethylamine (16.1 ,iL). To this suspension was transferred a solution of disuccinimidyl subarate (42.6 mg, 116 tmol) in dimethylformamide (200 tL). The resulting suspension was mixed at 1000 rpm under inert atmosphere for one hour. Thesuspension was centrifuged at 12,000 rpm for 1 minute, the supernatant was divided between three microtubes, and ether (ca. 1.8 mL per tube) was added. After 1 hr, the resulting suspension was centrifuged at 12,000 rpm for 3 minutes and the ether removed. The pellets were washed with ether (ca. 1.5 mL), centrifuged, the ether was removed, and the pellets were dried in vacuo. The pellets were washed with isopropyl alcohol (1500 ,iL), the denser precipitate was allowed tosettle, and the lighter precipitate (excess disuccinimidyl subarate) and isopropyl alcohol wash were removed and discarded. This wash was repeated once. The resulting precipitate was washed with ether (1 mL/tube), centrifuged for 3 minutes, the ether removed, and the pellets dried in vacuo to provide N-hydroxysuccinimide derivative 6-2 (10.9 mg, 73.4%). FTMS-pESI:calculated for C51H59N11O19Eu [M-Hf, 1280.3 193, found, 1280.3 198. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of H-GLU-OBZL (1.00 g, 4.21 mmol) in DMF (10.5 niL) was added triethylamine (5.875 mL, 42.1 mmol) followed by <strong>[68528-80-3]disuccinimidyl suberate</strong> (776 mg, 2.107 mmol). After stirring for 1 hour, the reaction mixture was concentrated and the resulting residue was purified on CI 8 column (ISCO 44 g), flow = 37 mL/min; gradient AcCN in water with 0.05%TFA: 2%-20% in 20 min followed by hold. After lyophilization, the intermediate bis- carboxylic acid was obtained. UPLC-MS Method B: Rt = 2.66 min, m/z = 613.3 [M+l]. | |
With triethylamine; In N,N-dimethyl-formamide; for 1h; | To a solution of H-GLU-OBZL (1.00 g, 4.21 mmol) in DMF (10.5 mL) was added triethylamine (5.875 mL, 42.1 mmol) followed by <strong>[68528-80-3]disuccinimidyl suberate</strong> (776 mg, 2.107 mmol). After stirring for 1 hour, the reaction mixture was concentrated and the resulting residue was purified on C18 column (ISCO 44 g), flow = 37 mL/min; gradient AcCN in water with 0.05%TFA: 2%-20% in 20 min followed by hold. After lyophilization, the intermediate bis- carboxylic acid was obtained. UPLC-MS Method B: Rt = 2.66 min, m/z = 613.3 [M+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; at 20 - 25℃; | 55 mg of the amine derivative was converted to the NHS ester by reacting with 168 mg <strong>[68528-80-3]octanedioic acid bis N-hydroxysuccinimide ester</strong>, 68 mu triethylamine in acetonitrile overnight at room temperature (RT). The protecting group was cleaved by addition of around lg Dowex 50WXH and continuously stirring until the reactio was completed. The product was purified by preparative HPLC. Yield 16 mg. HPLC-ESI-MS: M+ = 844.7 Da Synthesis of antigen conjugate: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
...preferably 15 amino acids.When sc(Fv)2 contains three peptide linkers, their length may be all the same or different.For example, such peptide linkers include:Synthetic linkers (chemical crosslinking agents) is routinely used to crosslink peptides, and for example:N-hydroxy succinimide (NHS),disuccinimidyl suberate (DSS),bis(sulfosuccinimidyl) suberate (BS3),dithiobis(succinimidyl propionate) (DSP),dithiobis(sulfosuccinimidyl propionate) (DTSSP),ethylene glycol bis(succinimidyl succinate) (EGS),ethylene glycol bis(sulfosuccinimidyl succinate) (sulfo-EGS),disuccinimidyl tartrate (DST), disulfosuccinimidyl tartrate (sulfo-DST), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Dimers Di-D8 were obtained by dimerization of 7 (i eq) using various bis-functional-amine-reactive reagents (0.5 eq) and NMM (S eq) inDMF (overnight). Bis-functional-amine-reactive reagents used were, for: p-nitrophenyl chloroformate (Di), suberic acid bi s(N-hydroxysuccinimide ester) (D2), i,S -difluoro-2,4-dinitrobenzene (D3),i,4-phenylene diisocyanate (D4), and4,4?-oxybis(phenyl isocyanate) (DS). Each compound was subsequently treated with 4 M HC1 in 1,4-dioxane for 30 mm to remove Boc protecting groups. Each solution was concentrated on rotary evaporator and Di-D6 were crystallized by addition of ice cold diethyl ether. Obtained crude Di-D8were purified by preparative reverse-phase high performance liquid chromatography (RPHPLC), and their purities were evaluated by matrix-assisted laser desorption ionization spectrometry (MALDI-MS) as well as analytical RP-HPLC (see Table Si). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5% | With triethylamine; In acetonitrile; at 20℃; for 4h; | A solution of (S)-tert-buty 2-amino-6-(((benzyloxy)carbonyl)amino) hexanoate hydrochloride (1.01 g, 2.71 mmol) in acetonitrile (50 mL) was added over a period of 30 min to a solution of bis (2,5-dioxopyrrolidin-l-yl) octanedioate (1.0 g, 2.71 mmol) and triethylamine (0.38 mL, 2.71 mmol) in acetonitrile (50 mL) and the mixture stirred at 20 C for 4 h. Acetonitrile was evaporated to reduce the volume to half and the remaining mixture was partitioned between water and ethyl acetate. Pooled ethyl acetate solution was dried with anhydrous sodium sulfate and concentrated. The crude product was purified using a Biotage 25 g SNAP ULTRA column and 7:3 hexanes:ethyl acetate as mobile phase to yield 1.0 g (1.70 mmol; 62.5%) of (S)-2,5- dioxopyrrolidin-l-yl 8-((6-(((benzyloxy)carbonyl)amino)-l-(tert-butoxy)-l- oxohexan-2-yl)amino)-8-oxooctanoate as a white solid: ^-NMR: deltapi (400 MHz, C2HC13) 7.38 - 7.25 (5H, m), 6.17-6.08 (1H, d), 5.06 (3H, m), 4.95-4.87 (1H, bs), 4.50-4.42 (1H, m), 3.38-3.30 (1H, m), 3.32-3.04 (4H, m), 2.86-2.72 (6H, m), 2.62- 2.52 (3H, m), 2.22-2.18 (2H, t), 1.81-1.06 (16H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.2 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere; | To a stirred solution of compound 13 (21.8 mg) in anhydrous DMF (500 iL) was added MM (7.8 mu.). This solution was then added dropwise over a period of 20 min to a stirred solution of <strong>[68528-80-3]suberic acid bis(N-hydroxysuccinimide ester)</strong> (43.8 mg) in anhydrous DMF (1.5 mL) at room temperature under an argon atmosphere. The reaction mixture was then stirred at room temperature for 20 h before the solution was concentrated in vacuo and purified by reverse phase C18-column chromatography, eluting with buffer A (v/v): water:0.05% trifluoroacetic acid and buffer B (v/v): acetonitrile:0.05% trifluoroacetic acid (90: 10 v/v to 0: 100 v/v). The organic solvent was removed in vacuo and the aqueous solvent removed by lyophilisation to give reagent 48 as a white solid (15.2 mg). m/z [M+Na]+ (2126, 10%), [M+H]+ (2104, 20%), [M+2Na]2+ (1074, 50%), [M+Na+H]2+ (1063, 50%) [M+2H]2+ (1052, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N,N',N'-tetramethylguanidine; In dimethyl sulfoxide; at 20℃; for 1h; | To a solution of RHI (331 mg, 0.057 mmol) in DMSO (6 mL) was added 1, 1,3,3- tetramethylguanidine (107 mu, 0.855 mmol), followed by dropwise addition of a solution of bis(2,5-dioxopyrrolidin-l-yl) octanedioate (10.5 mg, 0.029 mmol) in 0.16 mL DMSO (from a stock solution of 12.5 mg in 1 mL of DMSO) over 30 min. After stirred at rt for 0.5 h, the reaction solution was added dropwise into 20 mL of mixture of IP Ac/MTBE (4: 1) containing 0.5 mL HO Ac. The precipates were filtered and dried under N2 and vacuum overnight. Purification by reverse phase prep HPLC (C8 column, 50X250cm, 85ml/min, gradient from 29% to 38% of AcCN with 0.05% TFA in water with 0.05% TFA in 25 min). The selected fractions were lyophilyzed to isolate desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 1h; | Relative to the lysine-coated PSMA precursor (9B), 4 equiv of Dde as well as Fmoc protected L-lysine {(Dde-Lys(Fmoc)-OH; Merck; Catalog number 8540000001 ), 0.40 mmol, 532.63 g/mol, [213 mg] was activated with 3.96 equiv of HBTU {(Sigma; Catalog number 12804-25G-F), 0.396 mmol, 379.24 g/mol, [149 mg] in the presence of 4 equiv of DIPEA [0.40 mmol, 129.24 g/mol, 0.742 g/mL, [70 muL] in anhydrous DMF. Two min after the addition of DIPEA, the solution was added to the DMF pre-swollen immobilized bis(rt3u)- protected PSMA precursor (9B) and agitated for 1 h. The resulting compound (10B) was then washed three times with DMF1 and three times with DMF2. Selective removal of Fmoc-protecting group from the resulting compound (10B) was realized by washing with the mixture of DMF and piperidine in a ratio of 1 :1 once for 2 min and then once again for 5 min in order to obtain the product (11B). The conjugation of the chelator to the resin-immobilized compound (11B) was performed with 3 equiv of DOTA-tris(f-Bu)ester {([2-(4,7,10-tris(2-(t-butoxy)-2-oxoethyl)- 1 ,4,7,10-tetraazacyclododecan-1 -yl)acetic acid]; CheMatech; Catalog number 137076-54- 1 ), 0.30 mmol, 572.73 g/mol [171 mg]. The chelator building block was activated with 2.97 equiv of HBTU {(Sigma; Catalog number 12804-25G-F), 0.297 mmol, 379.24 g/mol, [112 mg] in the presence of 4 equiv of DIPEA {0.40 mmol, 129.24 g/mol, 0.742 g/mL, [70 muL] in anhydrous DMF. Two min after the addition of DIPEA, the solution was added to the resin-immobilized and the DMF pre-swollen compound (11 B). The coupling of the DOTA chelator proceeded over the course of 2 h with gentle agitation. The resulting compound (12B) was then washed three times with DMF1 and three times with DMF2. Selective removal of Dde-protecting group from the resulting compound (12B) was realized by washing with the mixture of 2 % hydrazine in DMF twice for 5 min and then once again for 10 min in order to obtain the product (13B). Relative to the resin-coated product (13B), 2 equiv of clisuccinimiclyl suberate {([suberic acid bis(/V-hydroxysuccinimide ester)]; Sigma; 68528-80-3), 0.20 mmol, 368.34 g/mol, [74 mg] was activated with 1 .98 equiv of HBTU {(Sigma; Catalog number 12804- 25G-F), 0.198 mmol, 379.24 g/mol, [73 mg] in the presence of 4 equiv of DIPEA {0.40 mmol, 129.24 g/mol, 0.742 g/mL, [70 muL] in anhydrous DMF. Two min after the addition of DIPEA, the solution was added to the resin-immobilized and DMF pre-swollen product (13B) and agitated for 1 h. The resulting compound (14B) was then washed three times with DMF1 and three times with DMF2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With triethylamine; In N,N-dimethyl-formamide; | Ligand L5 was prepared following a multi-step organic synthesis method as depicted in Scheme 4. A solution of la (0.190 g, 0.29 mmol), Epsilon Nu (0.029 g, 0.29 mmol) and DMF (1 mL) was added dropwise to a stirred solution of <strong>[68528-80-3]disuccinimidyl suberate</strong> (0.223 g, 0.61 mmol) in DMF (1 mL). The reaction mixture was stirred overnight, concentrated and purified by flash columnchromatography eluting with 30% acetonitrile/CH2Cl2provided 0.120 g (46%) of oily material. ESMS mlz: 911.3 (M + H)+. Compound 8 was prepared using the same method as described for 10. The crude product was purified by columnchromatography eluting with 40-60% acetonitrile/ CH2C12to provide 0.090 g (40%) of oily material. 'H NMR (500 MHz, CDCDMSO-c/6) delta ppm 7.70 (brs, 1H), 7.62 (d, J= 5.0 Hz, 1H), 7.55 (d, J = 10.0 Hz, 1H), 6.91 (d, J= 5.0 Hz, 1H), 6.85 (d, J = 5.0 Hz, 1H), 5.41 (d, J = 5.0 Hz, 1H), 5.33 (d, J= 10.0 Hz, 1H), 5.09-5.02 (m, 1H), 4.45- 4.35 (m, 2H), 4.25-4.19 (m, 3H), 3.41-3.34 (m, 1H), 3.12-3.05 (m, 2H), 2.57-2.50 (m, 2H), 2.31-2.18 (m, 5H), 1.97 (m, 1H), 1.86-1.77 (m, 3H), 1.71-1.63 (m, 5H), 1.57- 1.46 (m, 5H), 1.37 (m, 27 H); ESMS mlz: 957.2 (M + H)+. Compound 12 was prepared using the same method as described for 3a. The crude product was purified by C-18 column chromatography eluting with 40-50% acetonitrile/water to provide 0.057 g (58%) of product. ESMS mlz: 743.2 (M + H)+. Compound L6 was prepared using the same method as described for LI, using compounds la and 12 as the starting material. The reaction mixture was concentrated and purified by HPLC.XH NMR (500 MHz, DMSO-c/6) delta ppm 8.97 (brs, 1H), 8.43 (t, J= 5.0 Hz, 1H), 7.83 (d, J = 10.0 Hz, 2H), 7.78-7.73 (m, 1H), 7.56 (d, J= 10.0 Hz, 1H), 7.50 (d, J = 10.0 Hz, 2H), 7.38 (d, J = 10.0 Hz, 2H), 7.17-7.14 (m, 2H), 6.36-6.30 (m, 2H), 4.52-4.39 (m, 8H), 4.09-4.00 (m, 6H), 3.65-3.60 (m, 5H), 3.26-3.08 (m, 11H), 3.07-3.04 (m, 3H), 2.36-2.33 (m, 1H), 2.27-2.22 (m, 2H), 2.06-2.01 (m, 2H), 1.93-1.92 (m, 1H), 1.73- 1.64 (m, 2H), 1.51-1.43 (m, 11H), 1.26-1.19 (m, 6H); HRESI-MS: Calcd. for C55H82BrNioOi7, 1233.5037 [M+H]+, found: 1233.5029. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere; | Compound 3 (0.5g, 1.3 mmol) was dissolved in 10 mL anhydrous DMF in the presence of TEA (catalytic amount) and bis(2,5-dioxopyrrolidin-l-yl) octanedioate (4, lg, 2.7mmol) was added. The reaction mixture was stirred at room temperature for 24 hrs under argon atmosphere. After completion of the reaction (by TLC), excess diethyl ether (200 mL) was added to the reaction mixture. The white precipitate thus obtained was filtered and washed three times with cold diethyl ether (50 mL x 3). The crude product was purified by column chromatography on basic (TEA) silica gel (MeOH: CHC13 2:8 to 5:5 v/v) to give 5 (0.83g, 71% yield) as a low melting white solid. NMR (DMSO-d6): delta 7.94 (brs, 2H, NH X 2), 7.67 (brs, IH, NH), 6.41 (brs, IH, NH), 6.34 (brs, IH, NH), 4.29 (s, IH, CH), 4.12 (s, IH, CH), 3.06-3.04 (m, 3H, CH and CH2), 2.88-2.72 (m, 6H, CH2 X 3), 2.71-2.63 (m, 8H, CH2 X 4), 2.45-2.34 (m, 6H, CH2 X 3), 2.20-2.06 (m, 10H, CH2 X 5), 1.60-1.21 (m, 22H, CH2 X 1 1). (0258) 13C NMR (DMSO-d6): 172.5 (C=0), 170.7 (C=0), 163.1 (C=0), 162.7 (C=0), 61.4 (CH), 59.6 (CH), 55.8 (CH2), 53.9 (NCH2), 39.9 (CH2), 39.8(CH2), 39.6(CH2), 37.3(CH2), 36.2(CH2), 35.6(CH2), 31.2 (CH2), 28.7(CH2), 28.5(CH2), 25.8(CH2), 25.7(CH2), 25.6(CH2). (0259) ESI-MS: cald for C40H62N8O]2S, 878.4; found 901.3 (M +Na salt). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With trimethylamine; In dichloromethane; at 20℃; for 2h; | A solution of Boc-l ,5-diaminopentane (0.050 g, 0.25 mmol) and trimethylamine (0.1 mL, 0.72 mmol) in CH2CI2 (2 mL) was added dropwise to a solution of <strong>[68528-80-3]suberic acid bis-(N-hydroxysuccinimide ester)</strong> (DSS, 0.23 g, 0.62 mmol) in 3 mL CH2CI2, under mild stirring at room temperature. After 2 h, the solvent was evaporated. The crude material was purified on a silica column using a gradient from CH2CI2 to CH2CI2/CH3CN 1 : 1 to afford 0.072 g (64%) of compound 13. ESI-Mass calcd for C22H38N3O7 [M+H]+ 456.3, found 456.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With trimethylamine; In dichloromethane; at 20℃; for 2h; | A solution of H-Lys(Boc)-O^Bu HCl (0.2 g, 0.59 mmol) and trimethylamine (0.15 mL, 1.06 mmol) in CH2CI2 (6 mL) was added dropwise to a solution of <strong>[68528-80-3]suberic acid bis-(N-hydroxysuccinimide ester)</strong> (DSS, 0.7 g, 1.90 mmol) in 10 mL CH2CI2, under mild stirring at room temperature. After 2 h, the solvent was evaporated. The crude material was purified on a silica column using a gradient from CH2CI2 to CH2CI2/CH3CN 1 : 1 to afford 0.27 g (82%) of compound 11. ESI-Mass calcd for C27H45N309Na [M+Na]+ 578.3, found 578.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In butanone; at 20℃; for 12h; | (1) 100g of Bisuccinimide suberate,100 g of thioglycolic acid, 50 g of N,N-diisopropylethylamine, and 500 g of methyl ethyl ketone were mixed, and the mixture was stirred at room temperature for 12 hours to obtain a mixture; then, the mixture was washed with a 10% sodium chloride solution, and the organic layer was washed with sodium sulfate. Dry and evaporate the solvent,The residue was purified by precipitation in diethyl ether to afford intermediate (yield = 95%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | In dimethyl sulfoxide; at 20℃; | 94 mg (0.2 mmol) N4Py-propylamine (1) and 48 mg (0.1 mmol) 2-Aminoethylfolic acid gamma-amide (2) were dissolved in 10 mL DMSO with assistance of mild heating and sonication. A catalytic amount of triethylamine (0.04 mL) and 74 mg (0.2 mmol) DSS (3) were added successively and the mixture was stirred at r.t. overnight. The mixture was then filtered to remove any trace of solid residue and the filtrate was slowly added to vigorously stirred diethyl ether (100 mL). After standing for 1 minute, the ether was decantedcarefullyand the remaining sticky yellow solid was treated with another 100 mL diethyl ether and vigorous stirring. After decanting the ether, the sticky yellow solid was washed with 2x50 mL MeOH and 1x50 mL diethyl ether. After each washing step the suspension was homogenized using a sonication bath and the solid was collected by centrifugation (5 min, at 4000 rpm). 34 mg (0.03 mmol, 31%) of a bright yellow solid was obtained. For cell studies, an analytically pure sample was obtained by preparative RP-HPLC (linear gradient 90% B to 30% B in 40 minutes, flow: 1.0 mL/min, solvent A: acetonitrile B: ammonium formate 5 mM pH = 8.5). Analytical rp-HPLC (linear gradient 90% B to 30% B in 40 minutes, flow: 0.5 mL/min, solvent A: acetonitrile B: ammonium formate 5mM pH=8.5) TR= 24.7 min. LC-MS (ESI+) m/z: 1089.5 [M+H]+, 1111.5 [M+Na]+, 795.4 [M - Pteroic acid + 2H]+, 545.3 [M+2H]2+, 363.8 [M+3H]3+, 295.1 [Pteroic acid]+. HRMS (ESI+) calcd for C56H65N16O8+[M+H]+: 1089.517, found 1089.516. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Compound 5 (5 g, 14.6 mmol) prepared in the fifth step was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid.100ml (v:v=10:1),React at room temperature for 1 h,After the reaction is completed, the solvent is removed by spin drying.The residue was vacuum dried for 2 h.The dried residue was dissolved in 50 ml of dichloromethane, and 50 ml of a dichloromethane solution containing disuccinimide suberate (7.4 g, 20 mmol) was slowly added dropwise.Adding excess triethylamine,The reaction was carried out at room temperature for 3 h. After the reaction,Spin dry to remove solvent,Column chromatography purification (v dichloromethane: v methanol = 1000:1),6g light yellow powder compound NBS-1-8C,The yield was 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 6h;Inert atmosphere; | To a stirred solution of compound 3 (0.5 g, 1.3 mmol) and TEA(catalytic amount) in 10 mL anhydrous DMF was added <strong>[68528-80-3]disuccinimidyl suberate</strong> (4, 1 g, 2.7 mmol) and the reaction mixture stirred at room temperature for 6 h under a nitrogen atmosphere. After completion of the reaction, excess diethyl ether (200 mL) was added to the reaction mixture. The white precipitate thus obtained was filtered and washed 3 times with diethyl ether (50 mL×3). The crude product was purified by column chromatography on basic (TEA) silica gel (methanol:chloroform 2:8 to 5:5 v/v) to give 5 (0.83 g, 71% yield) as low meltingwhite solid. 1H NMR (DMSO-d6): delta 7.94 (brs, 2H, NH X 2), 7.67 (brs,1H, NH), 6.41 (brs, 1H, NH), 6.34 (brs, 1H, NH), 4.29 (s, 1H, CH), 4.12(s, 1H, CH), 3.06-3.04 (m, 3H, CH and CH2), 2.88-2.72 (m, 6H, CH2 X3), 2.71-2.63 (m, 8H, CH2 X 4), 2.45-2.34 (m, 6H, CH2 X 3), 2.20-2.06(m, 10H, CH2 X 5), 1.60-1.21 (m, 22H, CH2 X 11). 13C NMR (DMSO-d6):172.5 (C=O), 170.7 (C=O), 163.1 (C=O), 162.7 (C=O), 61.4 (CH),59.6 (CH), 55.8 (CH2), 53.9 (NCH2), 39.9 (CH2), 39.8(CH2), 39.6(CH2), 37.3(CH2), 36.2(CH2), 35.6(CH2), 31.2 (CH2), 28.7(CH2), 28.5(CH2),25.8(CH2), 25.7(CH2), 25.6(CH2). ESI-MS: calculated forC40H62N8O12S, 878.4; found 901.3 (M+Na salt). |
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H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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