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Structure of 108-00-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing
Li, Bowen ; Manan, Rajith Singh ; Liang, Shun-Qing ; Gordon, Akiva ; Jiang, Allen ; Varley, Andrew , et al.
Abstract: The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for mRNA and CRISPR-Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases.
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Purchased from AmBeed: 14916-80-4 ; 294-90-6 ; 13093-04-4 ; 65604-89-9 ; 22366-98-9 ; 143-28-2 ; 1484-84-0 ; 112-92-5 ; 3433-37-2 ; 34803-66-2 ; 622-26-4 ; 934-98-5 ; 3529-08-6 ; 123-70-6 ; 23356-96-9 ; 534-26-9 ; 20739-58-6 ; 4730-54-5 ; 108-00-9 ; 51388-00-2 ; 6711-48-4 ; 7209-38-3 ; 506-43-4 ; 2038-03-1 ; 142-25-6 ; 27578-60-5 ; 105-83-9 ; 67980-77-2 ; 877-96-3 ; 14712-23-3 ; 4572-03-6 ; 14156-95-7 ; 10563-26-5 ; 4097-88-5 ; 111-33-1 ; 123-12-6 ; 6261-22-9 ; 496808-04-9 ; 3644-18-6 ; 764-60-3 ; 1002-36-4 ; 51-45-6 ; 112086-54-1 ; 22104-79-6 ; 67529-83-3 ; 10563-29-8 ; 294-90-6 ; 506-43-4 ; 13901-38-7 ; 938459-02-0 ; 51721-39-2 ; 18128-28-4 ; 915922-79-1 ; 205059-32-1 ; 5298-72-6 ; 22763-69-5
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Photocatalytic α-arylation of cyclic ketones
Md Mubarak Hossain ; Aslam C. Shaikh ; Jules Moutet ; Thomas L. Gianetti ;
Abstract: The direct α-arylation of carbonyl compounds using aryl halides represents a powerful method to synthesize critical building blocks for diverse useful compounds. Numerous synthetic methods exist to forge C(sp2)–C(sp3) bonds although mild and metal-free direct α-arylation of ketones remains a challenging transformation. Here we report a green-light-mediated α-arylation of ketones from readily available aryl halides via activation of a C(sp2)–X bond (X = I, Br, Cl) and an α-carbonyl C(sp3)–H bond in a single photocatalytic cycle. This approach is characterized by its mild reaction conditions, operational simplicity and wide functional group tolerance. Importantly, the impressive outcome of the multigram photocatalytic reaction underpins the strength of this method as a potentially practical and attractive approach for scale-up industrial purposes. The utility and scope of this reaction were further demonstrated by formal syntheses of several feedstock chemicals that are commercially expensive but critical for synthesizing numerous pharmaceutical agents.
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CAS No. : | 108-00-9 |
Formula : | C4H12N2 |
M.W : | 88.15 |
SMILES Code : | NCCN(C)C |
MDL No. : | MFCD00008175 |
InChI Key : | DILRJUIACXKSQE-UHFFFAOYSA-N |
Pubchem ID : | 66053 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H225-H302-H314 |
Precautionary Statements: | P501-P270-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405 |
Class: | 3(8) |
UN#: | 2733 |
Packing Group: | Ⅱ |
Num. heavy atoms | 6 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 26.95 |
TPSA ? Topological Polar Surface Area: Calculated from |
29.26 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.42 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.68 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.49 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.18 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.87 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.16 |
Log S (ESOL):? ESOL: Topological method implemented from |
0.17 |
Solubility | 132.0 mg/ml ; 1.49 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.54 |
Solubility | 306.0 mg/ml ; 3.47 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.34 |
Solubility | 40.3 mg/ml ; 0.457 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.32 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.0 |
* 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 |
---|---|---|
25% | In DMF (N,N-dimethyl-formamide); at 20℃; for 15h; | A solution of the amine (1 equiv) and <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> [Windscheif, P-M.; Voegtle, F.; Synthesis 1994; 87-92] in DMF were stirred at room temperature for 15h. The solvent was removed under vacuum and the residue purified by silica gel chromatography. Examples a) R1 = dimethylaminoethyl The general procedure was followed using <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> (3.9 G) and dimethylamino ethylamine (5.5 g) in DMF (100 ML). Silica gel chromatography (4% MeOH in DCM) gave the pure product (0.62 g, 25%). LC-MS-SHOWS a single peak, M+H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 16h; | EXAMPLES Example 1.001(1) To a solution of tert-butoxycarbonyl-L-norvaline (1.50 g), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.99 g) and 1-hydroxybenzotriazole (933 mg) in chloroform (20 ml) were added N,N-dimethylethylenediamine (0.758 ml) and triethylamine (0.962 ml) in this order, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added water (30 ml), and the reaction mixture was stirred vigorously for 10 minutes, and the organic layer was separated. The aqueous layer was further extracted with chloroform. The organic layers were combined and washed with 1 percent EPO <DP n="22"/>aqueous potassium carbonate solution and saturated saline, and dried over anhydrous sodium sulfate, followed by removing the solvent under reduced pressure. The residue was purified by silica gel column chromatography [solvent: methanol-chloroform (1: 10)] to obtain N2-(tert- butoxycarbonyl)-N1-[2-(dimethylamino)ethyl]-L-norvalinamide (1.67 g). MS-APCI(m/z): 288 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydroxide; thionyl chloride; triethylamine; In dichloromethane; | EXAMPLE 4 (N,N-Dimethylaminoethyl)-2-Iodo-5-Nitro-Benzamide (1) <strong>[19230-50-3]2-iodo-5-nitro-benzoic acid</strong> (3 mmoles) was dissolved in a solution of dry dichloromethane-DMF mixture (v/v 4:1, 5 ml). To the ice-cold solution, was added 6 mmoles of thionyl chloride. The reaction mixture was stirred at room temperature for two hours. The solvent was then evaporated using a rotory evaporator. The residue was dried under vacuum at 50 C. for 30 minutes. The residue was dissolved in dry dichlormethane (5 ml) without any purification. The solution was then cooled to 0 C. To this solution, triethylamine (1 ml) and a solution of N,N-dimethylethylenediamine (3 mmole) in dichloromethane was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into water and basified to pH 12 using 2M NaOH. The organic layer was separated and washed with water, dried over anhydrous magnesium sulfate and concentrated. The (N,N-dimethylaminoethyl)-2-iodo-5-nitro-benzamide compound was separated by silica gel chromatography. The yield was 70%. The melting point was 126-128 C. 1H NMR (CDCl3) delta 2.27(s 6H, CH3); 2.55(t J=5.7 Hz, 2H, CH2N-); 3.55(q, J=5.7 Hz, 2H, CONHCH2-); 6.56(br s, 1H, NH); 7.93(dd, J=3.0 Hz, j=8.7 Hz, 1H, phenyl, H=4); 8.21(d, J=3.0 Hz, 1H, phenyl H=6) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 25℃; for 3h;Inert atmosphere; | Synthesis of 4-chloro-N-(2-(dimethylamino)ethyl)-3-nitrobenzenesulfonamide Into a 250-mL round-bottom flask under a nitrogen atmosphere, was placed a solution of (2- aminoethyl)dimethylamine (2 g, 22.69 mmol, 1 equiv) and triethylamine (4.6 g, 45.38 mmol,2.00 equiv) in anhydrous DCM (100 ml_). Then 4-chloro-3-nitrobenzene-1 -sulfonyl chloride (6.4 g, 24.96 mmol, 1 .10 equiv) was added at 0. The resulting solution was stirred for 3 hours at 25. The reaction was then quenched by the addition of 50 ml. of water/ice. The resulting solution was extracted with DCM (3 x50 ml_), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column eluting with dichloromethane/methanol (10:1 ). This resulted in 4-chloro-N-[2-(dimethylamino)ethyl]-3-nitrobenzene-1 -sulfonamide. | |
With triethylamine; In tetrahydrofuran; at -40 - 20℃; for 1h; | General procedure: A solution containing the appropriate aliphatic or cyclic amine substituent (1 equiv.) and triethylamine (2 equiv.) in THF was added dropwise to a solution containing 4-chloro-3-nitrobenzene-l-sulfonyl chloride 5 (1 equiv.) in TH F that was cooled down to -40C. After the addition was complete, the resulting mixture was allowed to warm up to room temperature over the course of one hour. Subsequently the reaction mixture was diluted with EtOAc and washed three times with water. The organic layer was dried using anhydrous sodium sulphate before being concentrated in vacuo. The crude reaction products 6-12 were used without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | General procedure: Method 2: to the solution of Indomethacin (100 mg, 0.28 mmol), the corresponding amine (0.28 mmol), and PyBOP (145.7 mg, 0.28 mmol) in anhydrous dimethylformamide was added triethylamine (56.5 mg, 0.56 mmol) and the mixture was stirred at room temperature for 2 h. Then saturated sodium chloride solution was added. The reaction mixture was extracted using ethyl acetate (3 x 50 ml). The combined organic layers werewashed successively with water, 5% aqueous sodium bicarbonate, and then concentrated under vacuum. The obtained crude product was purified by recrystallization or silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Method A: Synthesis of amide analogues (4). N-[2-(dimethylamino)ethyl]-12- oxo-12H-benzo[g]pyrido[2, l-b]quinazoline-4-carboxamide.To a solution of 12-oxo-12H- benzo[g]pyrido[2, l-b]quinazoline-4-carboxylic acid (50.mg, 0.17 mmol) and TBTU (82.9 mg, 0.26 mmol) in DMF (1 mL) was added DIPEA (90 mu, 0.52 mmol). After the contents were stirred at room temperature for 15 minutes, N,N-dimethylethylenediamine (28.4 mu^, 0.26 mmol) was added, and stirring continued for 16 hours (for convenience). Added reaction mixture to 100 mL cold water with stirring. Collected solid by filtration and dried under vacuum to give N-[2-(dimethylamino)ethyl]-12-oxo-12H-benzo[g]pyrido[2, l- b]quinazoline-4-carboxamide (36 mg, 0.10 mmol, 58.0 percent yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.50 (br. s., 1 H) 9.10 (s, 1 H) 8.91 (d, J=5.81 Hz, 1 H) 8.55 (d, J=5.56 Hz, 1 H) 8.28 - 8.34 (m, 2 H) 8.12 (d, J=8.34 Hz, 1 H) 7.73 (t, J=7.45 Hz, 1 H) 7.61 (t, J=7.33 Hz, 1 H) 7.05 (t, J=7.07 Hz, 1 H) 3.56 (d, J=5.05 Hz, 2 H) 2.59 (t, J=5.94 Hz, 2 H) 2.40 (s, 6 H). 1H NMR (400 MHz, CDC13) delta ppm 1 1.70 (br. s., 1 H) 9.10 (s, 1 H) 8.94 (dd, J=7.33, 1.77 Hz, 1 H) 8.73 (dd, J=6.82, 1.77 Hz, 1 H) 8.29 (s, 1 H) 8.12 (d, J=8.59 Hz, 1 H) 8.00 (d, J=8.34 Hz, 1 H) 7.66 (t, J=7.58 Hz, 1 H) 7.52 - 7.60 (m, 1 H) 6.89 (t, J=7.07 Hz, 1 H) 3.66 - 3.77 (m, 2 H) 2.71 (t, J=6.06 Hz, 2 H) 2.49 (s, 6 H). MS [M+l] = 361. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.92% | With boric acid; In toluene; for 24h;Reflux; | Thiophene amide was synthesized according to a published procedure.2,6 3-Thiophene acetic acid (0.711 g, 5.0 mmol) and boric acid (0.031 g, 0.5 mmol) were dissolved in toluene (100 mL), respectively. These two solutions were thoroughly mixed in a 250 mL round-bottom flask, after which N,N-dimethylethylenediamine (0.443 g, 5.0 mmol) was added in one portion. The resulting mixture was heated under reflux for 24 h, and the reaction was monitored by using TLC. The water was collected azeotropically in a Dean-Stark apparatus. After the reaction time, the mixture was cooled to 40-45 C, and excess boric acid was removed using filtration followed by further cooling to 25-35 C. After stirring for 1 h at 25-35 C, the toluene was decanted, and the resulting crude material was dissolved in methanol (50 mL). Distillation afforded (1.01 g, yield 94.92%) as a syrup. 1H nuclear magnetic resonance (1H NMR) (D2O, 400 MHz; Supporting Information Figure S1): δ 7.98 (t, 1H, N-H), 7.46 (s, 1H, thiophene moiety), 7.22 (d, 1H, thiophene moiety), 7.02 (d, 1H, thiophene moiety), 3.45 (s, 2H, -CH2), 3.19 (m, 2H, -CH2), 2.28 (m, 2H, -CH2), 2.106 (s, 6H, -CH3). Fourier transform infrared (FTIR) (KBr, Supporting Information Figure S2), υ 3280 cm-1 (N-H), 3070 cm-1(=C-H), 2910 cm-1 (C-H), 1640 cm-1 (C=O amide), 1520 cm-1 (N-H bond), 1450 cm-1 (C=C), 1125 cm-1 (C-N), and 750 cm-1 (C-S). High resolution mass spectrometry (HRMS) (electrospray ionization-mass spectrometry (ESI-MS), Supporting Information Figure S3) m/z calc. for C10H16Br2N2OS [M+ H]+, 213.31; found, 213.33. |
67% | 3-Thiopheneacetic acid (4.26 g, 30 mmol) was dissolved in 100 mL of anhydrous THF in a three-necked round bottom flask, followed by the addition of 5.88 g (36 mmol) of 1,1-Carbonyldiimidazole (CDI). The mixture was cooled in an ice-bath (0 C) and kept stirring for 20 minutes under a positive nitrogen flow. 3.28 mL of N,N’-dimethylethylenediamine (30 mmol) diluted in 10 mL of anhydrous THF was added dropwise with a dropping funnel. After the complete of addition, the mixture was warmed up to room temperature and kept stirring overnight. THF was removed with a rotary evaporator, and the product was purified with silica gel column chromatography (MeOH/CH2C12/ethyl acetate, 1/10/10 (v/v/v)). Pure product was obtained as a light yellowish liquid at 67 % yield. ‘H NMR (300 MHz, CDC13) ö7.31 (m, 1H), 7.15 (s, 1H), 7.02 (d, 1H, J= 4.8 Hz), 6.14 (s, 1H), 3.58 (s, 2H), 3.30 (m, 2H), 2.37 (t, 2H, J= 6.0 Hz), 2.18 (s, 6H) (FIG. 13). ‘3C NMR (300 MHz, CDC13) ö170.72, 135.26, 128.62, 126.38, 123.15, 57.89, 45.23, 38.29, 37.18 (FIG. 14). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | In ethanol; at 20℃; for 50h;Reflux; | <strong>[6492-86-0]4-amino-1,8-naphthalic anhydride</strong> (0.44 g, 2.07 mmol) was addedto a round bottom flask and dissolved in 290 mL of 200 proof ethanol,resulting in a clear, yellow-orange solution. The round bottom flask wastransferred to a sand bath and heated until boiling. N,N-dimethylethylenediamine(0.45 mL, 4.14 mmol) was added drop-wise to thenaphthalimide solution while then stirred at reflux for 2 h. The solutionthen stirred at room temperature for an additional 48 h, and the solventwas removed via rotary evaporation to yield the final product. (brownsolid, 0.58 g, 91.2%)1H NMR (400 MHz, d6-DMSO) 2.19 (s, 6H), 4.12 (t, J=7 Hz, 2H),6.84 (d, J=8 Hz, 1H), 7.44 (s, 2H), 7.65 (t, J=8 Hz, 1H), 8.19 (d,J=8 Hz, 1H), 8.43 (dd, J=1,7 Hz, 1H), 8.61 (dd, J=1,8 Hz, 1H). 13CNMR (400 MHz, d6-DMSO) 30.6, 39.9, 56.6, 107.5, 108.2, 119.3, 121.7,124.0, 129.3, 129.7, 130.8, 131.0, 134.0, 162.9, 163.8. FAB+;(M+H)+ calculated 284.1400, found 284.1393 (C16H18N3O2). |
60.1% | In ethanol; for 5h;Reflux; | 4-amino-1,8-naphthalene dicarboxylic anhydride (0.30 g, 1.4 mmol) and N, N-dimethylethylenediamine (0.88 g,10 mmol) was suspended in 20 mL of absolute ethanol, refluxed for 5 hours, concentrated to 5 mL, filtered, washed with ether, driedA light brown powder was obtained in a yield of 60.1%. No purification is required for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In N,N-dimethyl-formamide; at 20℃; | Compound 11a (5?mmol, 2.14?g) and N1,N1-dimethylethane-1,2-diamine (15?mmol, 1.32?g) in 15?mL DMF were stirred at room temperature overnight. The solvents were removed under vacuum and the residue was purified by silica gel flash chromatography (DCM: MeOH?=?10: 1) to give compound 14a (1.9?g, yield 79%).1H NMR (400MHz, DMSO-d6) delta 10.19 (s, 1H), 9.27 (s, 1H), 8.97 (s, 1H), 8.68 (s, 1H), 8.51-8.47 (m, 2H), 8.09 (s, 1H), 7.95 (s, 2H), 7.63-7.32 (m, 5H), 7.20 (s, 1H), 3.91 (s, 2H), 2.74 (s, 2H), 2.63 (s, 2H), 2.33 (s, 6H), 2.22 (s, 3H). 13C NMR (101MHz, DMSO-d6) delta 165.57, 162.07, 161.67, 159.94, 151.84, 148.66, 142.36, 138.25, 137.67, 134.90, 134.33, 132.69, 130.46, 128.86, 128.13, 124.25, 117.80, 117.32, 107.98, 57.17, 51.99, 45.07, 44.88, 18.13. HRMS (ESI, m/z) [M+H]+ calcd for C28H32N7O: 482.2668, found: 482.2663. |
In N,N-dimethyl-formamide; at 20℃; for 12h; | The 4 mmol of 4 - (chloromethyl) - N - (4 - methyl -3 - ((4 - (pyridine -3 - yl) pyrimidine -2 - yl) amino) phenyl) benzamide 2 and 12 mmol N, N - dimethyl ethylenediamine (purchase from buys from Alfa - Aesar) in 12 ml N, N - dimethyl formamide in, stirring at room temperature 12 hours. The rotary evaporator to remove the N, N - dimethyl formamide solvent, residue by silica gel chromatographic column to separate the product: 4 - ((2 - (dimethylamino) ethyl amino) methyl) - N - (4 - methyl -3 - ((4 - (pyridine -3 - yl) pyrimidine -2 - yl) amino) phenyl) benzamide 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In tetrahydrofuran; for 4h;Reflux; | In a 100 mL three-necked flask, limonoid (1 g, 2.13 mmol), N,N-dimethylethylenediamine (1.69 g, 19.19 mmol) and tetrahydrofuran (30 mL) were added and refluxed for 4 hours. The reaction was complete by TLC and a portion of the solvent was evaporated under reduced pressure. The residue was added with 100 mL of water and the pH was adjusted to acidic with 5% dilute hydrochloric acid. The aqueous layer was extracted three times with dichloromethane (80 mL × 3), and the combined organic layer was washed three times with saturated brine (100 mL × 3) and dried over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 100:1) to give 0.68 g of a white solid (I-11). The yield was 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | The resin-bound peptide prepared in Example 2 (0.32 mmol) was treated K2C03 (88 mg, .64 mmol) and3 x 1 hour cycles of 5% thiophenol in DMF. After each treatment, the resin was filtered and washed with DMF. Complete conversion wasconfirmed by LCMS and a positive Kaiser test. LCMS analysis - ESI mlz+ observed:1302.7, required for [C64H107N11017 + H]b:1302.8.The resin was then treated with a solution of <strong>[123639-61-2]Fmoc-Glu(OBzl)</strong>-OH (294 mg, 0.64 mmol), HBTU (99 mg, 0.64 mmol), and TEA (200 tL, 1.28 mmol) in DMF (5 mE). After the reaction was mixed for 60 minutes, the resin was filtered and washed withDMF. Complete conversion was confirmed by a negative Kaiser test.The resin-bound peptide obtained above was next treated with 20% piperidine in DMF for two 15 minute cycles, after which the resin was washed thoroughly with DMF and CH2C12. The peptide was then cleaved from the resin by 3 x 30-minute treatments with 30% HFIP in CH2C12, collecting the filtrate after each treatment. The filtrate wasconcentrated and the desired peptide was isolated by reverse phase flash chromatography. (Column: Puriflash 15 tM C18 120 g, Gradient: 30-70% B over 20 minutes at 50 mL/min). Yield - 88 mg (0.058 mmol). LCMS analysis - ESI mIz observed: 1521.6, required for [C76H120N12020 + H]: 1521.9.The purified peptide obtained above (88 mg, 0.05 8 mmol) was dissolved inCH2C12 (50 mL) and DMF (15 mL) with i-Pr2NEt (36 tL, 0.208 mmol) and cooled to0C. The solution was then treated with a solution of HBTU (26 mg, 0.069 mmol) in DMF (1 mL) and allowed to react for 30 minutes. Complete cyclization conversion was confirmed by LCMS analysis. The reaction solution was transfeffed to a separatory funnel and extracted with aqueous NaHCO3 and Brine. The organic phase was collectedand dried over magnesium sulfate, after which the solution was filtered and concentrated in vacuo. The crude product residue was used without purification. LCMS analysis - ESI mIz observed: 1504.2, required for [C76H118N12019 + Hib: 1503.9.A solution of the crude cyclized peptide in MeOH (10 mL) was charged with 10% palladium on carbon (31 mg). The reaction flask was then sealed with a septum andpurged with hydrogen gas. After the reaction was allowed to proceed under a slight positive pressure of hydrogen for one hour, the reaction was filtered to remove palladium on carbon. Complete conversion was confirmed by LCMS analysis. The filtered reaction solution was concentrated in vacuo and the remaining oily residue was taken up in 1: 1 acetonitrile/water, which produced a white precipitate. The precipitate wasremoved by filtration and the filtrate containing the desired product was concentrated in vacuo. The crude product residue was used without purification. LCMS analysis - ESI mIz observed: 1413.8, required for [C69H112N12019 + Hib: 1413.8.The crude Glu-deprotected peptide was either treated with TFA in order to achieve global deprotection or alternatively, a solution of the peptide (26 mg, 0.018mmol) in CH2C12 (1 mL) and i-Pr2NEt (12 tL, 0.066 mmol) in DCM (1 mL) was treated with 100 mM HBTU in DMF (220 tL, 0.022 mmol) and allowed to react for 15 minutes. N,N-dimethylethylenediamine (4 tL, 0.036 mmol) was then added. After 1 hour, the reaction was diluted with ethyl acetate ( 15 mL) and extracted with aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate and thenfiltered and concentrated in vacuo. After the resulting residue was treated with TFA and allowed to react for 1 hour, the solvent was removed and the product was purified by preparative reverse phase HPLC (Column: Luna 5 tm C18, 100 x 30 mm; Gradient 20- 40% B over 20 minutes at 40 mL/min). Fractions containing the product were combined and lyophilized to provide the product as a white powder. Yield: 11.7 mg, 0.00772 mmol(Di-TFA salt), 2% overall yield from starting resin. LCMS analysis - ESI mIz observed:1287.7, required for [C61H102N14016 + H]: 1287.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | General procedure: Ethyl 4-hydroxyquinoline-2-carboxylate (3) (1.0 mmol), N1,N1-dimethylethane-1,2-diamine(2.0 mmol, to achieve 4), or N1,N1-dimethylpropane-1,3-diamine (2.0 mmol, to achieve 5) wereplaced in a 50 mL round bottom flask. The mixture was refluxed in 30 mL EtOH for 7-8 h. Afterthe evaporation of the solvent, the residues were crystallized with Et2O (10 mL). The products weredissolved in 15 mL of EtOH and HCl/EtOH (22%) was added until reaching pH = 1. Et2O (10 mL) wasadded to the solution until precipitation. The crystals were filtered and washed with 2 15 mL Et2Oyielding 4 or 5, respectively.N-(2-(dimethylamino)ethyl)-4-hydroxyquinoline-2-carboxamide hydrochloride (4). Yield: 241 mg (82%); m.p.150-153 C. 1H-NMR (D2O); 3.03 (6H, s); 3.50 (2H, t, J = 6.0 Hz); 3.88 (2H, t, J = 6.1 Hz); 6.80 (1H, s); 7.54(1H, t, J = 7.4 Hz); 7.76 (1H, d, J = 8.3 Hz); 7.83 (1H, t, J = 7.9 Hz); 8.12 (1H, d, J = 8.3 Hz); 13C-NMR (D2O);35.3; 43.2; 53.4; 106.8; 119.4; 124.3; 124.7; 125.8; 134.0; 139.4; 141.7; 163.7; 180.3; ppm. C14H18ClN3O2(295.76): calcd. C, 56.80; H, 6.09; N, 14.20; found C, 56.73; H, 6.08; N, 14.16. |