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CAS No. : | 506-32-1 | MDL No. : | MFCD00004417 |
Formula : | C20H32O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YZXBAPSDXZZRGB-DOFZRALJSA-N |
M.W : | 304.47 | Pubchem ID : | 444899 |
Synonyms : |
Immunocytophyt;Eicosatetraenoic acid (all cis-5,8,11,14);C20:4 (all cis-5,8,11,14) Fatty acid;Arachidonic acid (all cis-5,8,11,14);Arachidonate
|
Num. heavy atoms : | 22 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.55 |
Num. rotatable bonds : | 14 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 98.13 |
TPSA : | 37.3 Ų |
GI absorption : | None |
BBB permeant : | None |
P-gp substrate : | None |
CYP1A2 inhibitor : | None |
CYP2C19 inhibitor : | None |
CYP2C9 inhibitor : | None |
CYP2D6 inhibitor : | None |
CYP3A4 inhibitor : | None |
Log Kp (skin permeation) : | None cm/s |
Log Po/w (iLOGP) : | None |
Log Po/w (XLOGP3) : | None |
Log Po/w (WLOGP) : | 6.22 |
Log Po/w (MLOGP) : | None |
Log Po/w (SILICOS-IT) : | None |
Consensus Log Po/w : | None |
Lipinski : | None |
Ghose : | None |
Veber : | None |
Egan : | None |
Muegge : | None |
Bioavailability Score : | None |
Log S (ESOL) : | None |
Solubility : | None mg/ml ; None mol/l |
Class : | None |
Log S (Ali) : | None |
Solubility : | None mg/ml ; None mol/l |
Class : | None |
Log S (SILICOS-IT) : | None |
Solubility : | None mg/ml ; None mol/l |
Class : | None |
PAINS : | None alert |
Brenk : | None alert |
Leadlikeness : | None |
Synthetic accessibility : | None |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313 | UN#: | N/A |
Hazard Statements: | H315-H319 | 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 |
---|---|---|
100% | With lithium aluminium tetrahydride In diethyl ether 1.) 30 min, 10 deg C, 2.) 30 min, reflux; | |
99% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; | |
99% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: With water; sodium hydroxide In tetrahydrofuran for 1h; | 3 Example 3(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraen-1-ol To a suspension of LiAlH4 (0.499 g, 13.14 mmol) in dry THF (50 mL) was added arachidonic acid (1.00 g, 3.28 g) in dry THF (40 mL) at 0° C. (ice-bath) under argon and the reaction mixture was stirred for 1 h at 0° C. and then for 1 h at room temperature. After a slow addition of water (0.2 mL), the white gelatinious precipitate was dissolved by adding 10% aq NaOH (0.2 mL) and water (0.6 mL) and the mixture was allowed to stir for 1 h. The mixture was then dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure to furnish a crude, which was purified over silica-gel column chromatography using 20% ethyl acetate/hexane to give the product as a clear oil (0.945 g, 99%). 1H NMR (CDCl3): δ5.37 (m, 8H), 3.64 (t, 2H, J=6.4 Hz), 2.81 (m, 6H), 2.09 (m, 4H), 1.61 (m, 2H), 1.50-1.30 (m, 8H), 1.04 (t, 3H, J=6.8 Hz). m/z (APCI) 291.43 (M++1). |
84% | With lithium aluminium tetrahydride In diethyl ether at 20℃; for 1h; | |
80% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 2h; Cooling with ice; Stage #2: With water; sodium hydroxide In tetrahydrofuran for 1h; | [00109j 4,7,10,13,16,1 9-all-cis-docosahexaenoic acid (DHA), 4,7,10,13,16,1 9all-cis- docosahexaenoic acid methyl ester (DHA-me), 5,8,11,14,1 7zll-cis-eicosapentaenoic acid (EPA), and methyl 9-cis-octadecenoic acid (oleic acid) were purchased from Sigma-Aldrich. Docosahexaenoyl glycine andN-arachidonoyl taurine were purchased from Cayman Chemical. Synthesis of arachidonyl amine (Scheme 1) was performed as described Borjesson et al.cell Biochem Biophys 52, 149-174 (2008), S.I., Parkkari, T., Hammarström, S. & Elinder, F. Electrostatic Tuning of Cellular Excitability.Biophys J 98, 396-403 (2010). Arachidonic acid (Nu Chek prep, mc) was used as a starting material to produce arachidonyl alcohol. For synthesis of arachidonyl alcohol, LiA1H4 (0.5 g, 13 mmol) was suspended into dry tetrahydrofuran (THF, 50 mL) and the mixture was cooled on an ice bath. Arachidonic acid (1.1 g, 3.5 mmol) in dry THF (40 mL) was added slowly. After the addition, stirring was continued for 1 hour on the ice bath and an additional hour at room temperature. Ice cold water (1 mL) following 10% NaOH (0.2 mL) was added slowly and stirring was continued for 1 hour. The mixture was filtered through Celite and the filtrate was dried over NSO4. Evaporation of solvents gave 800 mg (80%) of a colorless, oily product. ‘HNMR (CDC13): ö 0.89 (t, 3J=3 .6 Hz, 3H), 1.19 (t, 3J=2.5 Hz, 1H) 1.25 - 1.39 (m, 6H), 1.42- 1.48 (m, 2H), 1.57- 1.62 (m, 2H), 2.04-2.13 (m, 4H), 2.80-2.85 (m, 6H), 3.66 (q,3J=6.0 Hz, 2H), 5.31 -5.43 (m, 8H). |
With pyridine; methanol; sodium tetrahydroborate; trifluoro-[1,3,5]triazine 1.) CH2Cl2, -20 to -010 deg C, 1 h, 2.) room temperature, 10-15 min; Yield given. Multistep reaction; | ||
With lithium aluminium tetrahydride In diethyl ether at 0℃; | ||
With lithium aluminium tetrahydride In diethyl ether at 10℃; for 1h; Reflux; | ||
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 3h; | ||
Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 0.33 h / 0 °C / Inert atmosphere 2.1: sodium tetrahydroborate / tetrahydrofuran; water / 0.02 h / -8 °C / Inert atmosphere 2.2: 0.67 h / -8 - 20 °C / Inert atmosphere | ||
With lithium aluminium tetrahydride In tetrahydrofuran Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 2,6-dimethylpyridine; iodine In dichloromethane at 0℃; for 15h; Inert atmosphere; Cooling with ice; | 4.2. Iodolactonization of EPA, AA and DHA (method A) General procedure: Prepared according to literature procedure by Ulven and coworkers.27 A solution of 2,6-lutidine (2.00 equiv.) in CH2Cl2 (18.0 mL/g2,6-lutidine) was added dropwise to the acid (1.00 equiv.) and thencooled to 0 °C under an argon atmosphere. An ice cold solution of I2(2.00 equiv.) in CH2Cl2 (final concentration of 70.0 mM) was added andthe stirring was continued overnight (15 h) at 0 °C. The reaction wasquenched by the addition of aqueous Na2S2O3 and extracted with ethylacetate (3×). The combined organic layers were washed with saturatedaqueous NaH2PO4 (3×), brine and dried (Na2SO4). The solvent wasremoved in vacuo and the product was passed through a short silicaplug (heptane/EtOAc 1:1) to afford the iodolactone. |
83% | With 2,4,6-trimethyl-pyridine; iodine In dichloromethane at 0℃; for 14h; | lodolactonization of arachidonic acid:6-((3Z,6Z,92^-1 -lodopentadeca-3,6,9-trien-1 -yl)tetrahydro-2H-pyran-2-one (2). An ice cold solution of arachidonic acid 1 (400 mg, 1 .31 mmol) and γ-collidine (320 mg, 2.64 mmol) in CH2CI2 (20 mL) was added iodine (672 mg, 2.65 mmol). The reaction mixture was stirred for 14 h at 0 °C. The mixture was diluted with CH2CI2 (50 mL) and washed with 5% aqueous Na2S203, aqueous KHS04 (0.5 M) and brine. The organic layer was dried over anhydrous Na2S04 and concentrated under vacuum. The residue was purified by flash chromatography (Si02, 6% EtOAc in petroleum ether) to yield 493 mg (83%) of 2 as a colorless oil: 1H NMR (400 MHz, CDCI3) δ 5.61-5.50 (m, 1 H, H-9'), 5.46-5.28 (m, 5H, H-3', 4', 6', 7' & 10'), 4.10 (td, J = 7.4, 2.6 Hz, 1 H, H-1 '), 3.96 (dt, J = 10.7, 3.1 Hz , 1 H, H-3), 2.88-2.76 (m, 6H, H-2', 5' & 8'), 2.69-2.44 (m, 2H, H-6), 2.10-1 .78 (m, 6H, H- 4, 5 & 1 1 '), 1 .41-1 .23 (m, 6H, H-12', 13' & 14'), 0.89 (t, J = 6.9 Hz, 3H, C-15'); 13C NMR (101 MHz, CDCIs) δ 170.4 (CO), 131 .5 (C-9'), 130.6, 129.2, 127.4, 127.2, 127.1 , 81 .0 (C-3'), 36.8 (C-1 '), 34.4, 31 .5 (C-14'), 29.6 (C-6), 29.3, 28.0, 27.3 (C-1 1 '). 25.9, 25.7, 22.6, 18.3, 14.1 (C-15'); HMDS m/z calcd for C2oH3i02INa (M + Na+) 453.1262, found 453.1256. |
62% | With potassium hydrogencarbonate In ethanol; hexane; water at 24℃; for 16h; |
With potassium triiodide; potassium hydrogencarbonate In tetrahydrofuran; water at 0℃; | ||
5 g | With iodine; sodium hydrogencarbonate In ethanol | 12.2 Step 2: lodolactonisation The crude arachidonic acid produced in step 1 was dissolved in ethanol (35 ml, 80%) and added to a saturated aqueous solution of NaHCO3 (15 ml). An ethanoic solution (80 ml, 95%) of iodine (2.59 g) was added dropwise under vigorous stirring within an hour. Additional iodine (2g) was added after 1.5 hrs reaction time. The mixture was left stirring overnight and Na25203 was added until the solution was colorless. The mixture was extracted with hexane (3x100 ml) and the combined organic layer washed with water, brine and dried (MgSO4). Filtration and evaporation gave the crude iodolactone (5g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalyl dichloride; N,N-dimethyl-formamide In benzene Ambient temperature; | ||
With oxalyl dichloride | ||
With oxalyl dichloride; N,N-dimethyl-formamide In benzene |
With oxalyl dichloride for 3h; | ||
With oxalyl dichloride In N,N-dimethyl-formamide; benzene at 25℃; for 1h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In benzene at 0 - 5℃; for 1h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 1h; | ||
With oxalyl dichloride In benzene at 0 - 20℃; | ||
With oxalyl dichloride In N,N-dimethyl-formamide; benzene at 0℃; for 1h; | ||
With thionyl chloride In benzene at 23℃; for 2h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25℃; | ||
With oxalyl dichloride In benzene | ||
With oxalyl dichloride In N,N-dimethyl-formamide | ||
With thionyl chloride; Amberlyst A-21 In dichloromethane at 20℃; for 1h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | ||
With oxalyl dichloride In dichloromethane at 0℃; for 2h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | ||
With oxalyl dichloride In dichloromethane at 20℃; | 4; 5 Synthesis Example 4 Triarachidin (Glycerol trieicosotetra5-Z, 8-Z, 11-Z, 14Z-ENEOATE) or AAA Arachidonic acid (50.9 g, 0.17 mol, 3 EQ) was dissolved in dichloromethane (DCM, 175 ml) and stirred at room temperature under a nitrogen atmosphere. Oxalyl Chloride (21.9 ml, 31.9 g, 0.25 mol, 4.4 eq) was then added to the stirred solution over 5 min and the temperature increased by 4 C. THE resulting yellow-green mixture was stirred at RT overnight and then concentrated in vacuo to remove DCM and excess oxalyl chloride. The residual oily acid chloride (A-C1) was then added dropwise over 15 min to a pre-warmed (25 °C) stirred mixture of glycerol (5.11 g, 0.055 mol, 1 eq), pyridine (13.5 ml, 13.2 g, 0.17 mol, 3 eq) and 4-dimethylamino pyridine (DMAP, 0.20 g, 0.002 mol, 0. 03 eq). The temperature of the reaction mixture rose to 42 °C during the addition and a gentle reflux was observed. The mixture was stirred at 30-40 °C and monitored by HPLC. After 2 H, no further product formation was observed. The precipitated pyridine hydrochloride was filtered off and washed with DCM. The combined filtrate and washings were then washed with 1 x 50 ml portions of 5% NaCl, 5% NAHC03, O. 1N HCI, 5% NaCl. The solution was then dried over MGSO¢ and concentrated in vacuo to give the crude product as a yellow-orange oil (57 g). This oil was purified by column chromatography on silica gel (CA. 600 g). Elution with hexane and diethyl ether (2-4%)-hexane gave 22.8 g of the product as an oil. A second batch (17.8 g) was produced from 39.8 g of arachidonic acid, The two batches were combined and residual solvents removed under vacuo to give 40.5 g (43%) of a mobile pale yellow oil. HPLC purity 84.8% GLC analysis 94.3% AA (arachidonic acid).; 1, 3-DICAPRIN 2-arachidonate (CAC) Arachidonic acid (AA96,8. 34 g, 0.03 mol) was dissolved in dichloromethane (DCM, 60 ml). The resulting solution was stirred at RT under nitrogen and oxalyl chloride (3.9 ML, 5.67 g, 0.044 mol) added dropwise over 5 mins. The mixture was stirred at RT overnight and then concentrated in vacuo to remove DCM and excess oxalyl chloride. The residual oily acid chloride (GLA-C1) was then added dropwise over 15 min (ice/water cooling) to a stirred solution of 1,3-dicaprin (11. 2g, 0. 028 mol), DCM (50 ml), pyridine (2.42 ml, 2.37 g, 0.03 mol) and 4- dimethylaminopyridine (0.10 g, 0.0008 mol, 0.03 equiv) at 10-15°C. The temperature was maintained by ice-water cooling. The reaction mixture was stirred at RT under nitrogen overnight. Pyridine hydrochloride was removed by filtration and washed with DCM. The combined washing and filtrate was washed with 1 x 20ML portions of 5% NACL, 5°/ONAHCO3, O. 1N HCL, 5°/ONAC1. The solution was then dried over MGS04 and the solvent removed in vacuo. The residual brown oil was purified by column chromatography on silica. Elution with hexane and then with 5% ether/hexane gave 10.3g (56%) of a colourless oil. The structure was confirmed by 13C NMR and GLC. | |
With oxalyl dichloride In benzene at 20℃; for 2.5h; | R.1 Reference Example 1 Synthesis of 6-O-arachidonoyl-ascorbate Arachidonic acid (2.0 g, 6.6 mmol) was dissolved in benzene (20 ml). To this solution, oxalyl chloride (5.4 ml, 7.9 mmol) was added and the mixture was stirred at room temperature in a nitrogen atmosphere for 2.5 hours. Subsequently, the mixture was concentrated under reduced pressure to obtain arachidonyl chloride as an oily product. Meanwhile, L-ascorbic acid (1.4 g, 7.9 mmol) was added to a mixture of N-methylpyrrolidone (15 ml) and 4N-HCl/dioxane (2.4 ml) and the mixture was chilled on ice. To this solution, the arachidonyl chloride in methylene chloride (approx. 2 ml) was added, and the mixture was stirred overnight while chilled on ice. Upon completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water (twice), was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluant=methanol/methylene chloride (1% to 20% methanol gradient)) and was dried under reduced pressure to give the desired product as a paste (2.7 g, 90% yield). PMR(d ppm, CDCl3); 0.87 (3H, t), 1.2-1.4 (6H, m), 1.73 (2H, q), 2.0-2.2 (4H, m), 2.36 (2H, t), 2.8-2.9 (6H, 4.2-4.3 (3H, m), 4.79 (1H, s), 5.36 (8H, m). | |
With oxalyl dichloride In benzene at 20℃; for 2.5h; | 1 Arachidonic acid (2.0 g, 6.6 mmol) was dissolved in benzene (20 ml) and after addition of oxalyl chloride (5.4 ml, 7.9 mmol), the mixture was stirred for 2.5 hours at room temperature in a nitrogen atmosphere. Subsequent concentrating under reduced pressure gave an oil of arachidonyl chloride. To a solution of N-methylpyrrolidone (15 ml) in a 4N HCl/dioxane mixture (2.4 ml), L-ascorbic acid (1.4 g, 7.9 mmol) was added and the solution was cooled with ice. To the ice-cooled solution, a solution (ca. 2 ml) of the already prepared arachidonyl chloride in methylene chloride was added and the mixture was stirred overnight under cooling with ice. After the end of the reaction, water was added and extraction with ethyl acetate was performed. The ethyl acetate layer was washed with water (twice), dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluant, l%-20% gradient) and evaporated to dryness under reduced pressure to give a paste of the titled compound (2.7 g, yield: 90%). PMR((5ppϖκ CDCl3); 0.87(3H, t), 1.2-1.4(6H, m) , 1.73(2H, q) , 2.0-2.2(4H, m) , 2.36(2H, t), 2.8-2.9(6H, 4.2-4.3(3H, m) , 4.79(1H, s), 5.36(8H, m)o | |
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran for 0.916667h; Cooling with ice; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; | ||
With oxalyl dichloride In benzene at 0 - 20℃; | A Chemical Synthesis of Compound 3 The chemical synthesis of Compound 3 from arachidonic acid (Compound 1) is also illustrated in Reaction Scheme 1. Compound 3 is synthesized by modification of procedures reported by Ryan et al. J. Med. Chem. 1997, 40, 3617-3625, based on previous work by Corey et al. Tetrahedron Lett. 1983, 24, 37-40 and Manna et al. Tetrahedron Lett. 1983, 24, 33-36. The Ryan et al., Corey et al., and Manna et al. publications are hereby expressly incorporated by reference. To a 0.4 M solution of arachidonic acid (Compound 1) in anhydrous benzene at 0° C. are added two equivalents of oxalyl chloride. The mixture is stirred for overnight while allowed to warm to room temperature. The solvent and excess oxalyl chloride is removed in vacuo. The resulting crude acid chloride is dissolved in anhydrous THF to make a 2 M solution. Half an equivalent of pyridine is added to the above solution and the mixture is stirred for 10 min at 0° C. 0.7 M solution of LiOH.H2O in 50% H2O2 containing one equivalent of LiOH.H2O is added and the mixture is stirred for 20 min. The reaction is quenched with pH 7 buffer and brine and extracted with CH2Cl2 (×3). The combined organic layer is washed with brine and dried over Na2SO4. During this time the epoxy acid is formed and its formation can be monitored by TLC analysis. Upon completion, the drying agent is removed by filtration and the solvent is removed in vacuo. The residue is dissolved in anhydrous Et2O and treated with excess diazomethane. After stirring for 15 min, excess diazomethane is evaporated in a fume hood at room temperature and the solvent is removed in vacuo. The crude product is purified by chromatography on silica gel. | |
With oxalyl dichloride In dichloromethane at 65℃; for 0.0833333h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In benzene at 0℃; for 1h; | Arachidonoyl-4-methylaminoantipyrin (5; (5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoic acid (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-methyl-amide). Arachidonic acid (0.200 g, 0.66 mmol) and dimethylformamide p.a. (48 mg, 0.66 mmol) were dissolved in benzene p.a. (5 ml). The mixture was cooled to 0 °C, 2 equiv of oxalyl chloride (0.168 g, 2.0 mmol) were added dropwise, and stirring was continued for 1 h at 0 °C. After dilution with tetrahydrofurane p.a. (THF, 5 ml), methylaminoantipyrine (2) (0.717 g, 3.3 mmol) was added in 5 ml THF solution. The mixture was stirred for another 15 min, diluted with dichloromethane, and washed with aqueous 10% HCl, 1 M NaOH and water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography on normal phase silica gel (40-63 μm), eluting with CHCl3/EtOH (9+1). Yield, 0.223 g (67%) of a slightly greenish oil. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 0.5h; Inert atmosphere; | cis-Arachidonoylbenzylidene glycerol (cis-ABG) Under anhydrous conditions, arachidonic acid (75 mg, 0.25 mmol) in 3 mL dry CH2Cl2 was cooled under nitrogen to 0 °C and treated with oxalyl chloride in CH2Cl2 (0.45 mL of 2.0 M) and two drops of DMF to produce gas evolution. The solution was stirred for 30 min at room temperature, and an aliquot was quenched with MeOH and analyzed by TLC (SiO2, EtOAc/hexane 2:3, phosphomolybdic acid detection). Methyl arachidonate but no arachidonic acid was observed, indicating complete conversion to the arachidonoyl chloride). The volatiles were removed in vacuo and the residue blanketed with nitrogen and dissolved in 3 mL of dry CH2Cl2 and cooled to -72 °C. Pyridine (45 mg, 0.57 mmol) was added followed by cis-O-benzylidene glycerol (88 mg, 0.49 mmol, 2 equiv) in 2 mL of CH2Cl2. The reaction was stirred and warmed to room temperature overnight under N2 and then filtered through a 1 g SiO2 Sep-Pak followed by elution with 3 mL CH2Cl2. Chromatography of the product concentrate on another 1 g SiO2 Sep-Pak eluting with 5 mL CH2Cl2 afforded 91 mg of cis-ABG as a resin, (0.188 mmol, 76% TY). | |
With thionyl chloride In benzene at 20℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0℃; for 1h; | 2.6 Substances Arachidonic acid (201mg, 0.66mmol) and dimethylformamide (48.2mg, 0.66mmol) were dissolved in dry tetrahydrofurane (10ml). The mixture was cooled to 0°C, two equivalents of oxalyl chloride (167.5mg, 1.32mmol) were added dropwise, and stirring was continued for 1h at 0°C. A solution of aminoantipyrine (3, 670.7mg, 3.3mmol) in 5ml of dichloromethane was added and stirring continued for further 30min at ambient temperature. The mixture was washed with aqueous 0.1M HCl, satured aqueous sodium hydrogen carbonate solution and saline. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography on normal phase silica gel (40-63µm), eluting with ethyl acetate/methanol (98/2). Yield, 179.7mg (54%). | |
With oxalyl dichloride In dichloromethane at 20℃; for 3h; | General Procedure for Preparation of N-Acylhistamines (N-Acyl-HAs) General procedure: A solution of fatty acid acyl chloride (1.0 mmol), purchased from Tokyo Chemical Industory (Tokyo, Japan), in N,N-dimethylformamide (DMF) (2 mL) was added dropwise to a suspension of histamine dihydrochlolide (2.0 mmol) and Et3N (8 mmol) in DMF (5 mL) cooled in an ice bath. In some cases (i.e., for the C18:1, C18:2 and C20:4 analogues), the acyl chlorides were prepared by reacting the free fatty acids with oxalyl chloride (5 eq, CH2Cl2, r.t., 3 h). The reaction mixture was stirred for 5 h at room temperature. Ice water was added to the mixture and the reaction mix was extracted with CHCl3. The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 : MeOH : aq. NH3=20 : 1 : 0.5) to give the corresponding N-acylhistamine. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | ||
With thionyl chloride In dichloromethane at 20℃; Inert atmosphere; | 4.1.8. N-arachidonoyl Serinol (9) General procedure: A solution of Z,Z,Z,Z-5,8,11,14-eicosatetraenoic acid (arachidonic acid) (510 mg, 1.5 mmol) andthionyl chloride (87 mmol, 6.3 mL) in dry dichloromethane (10 mL) was stirred at room temperatureunder argon atmosphere until the reaction is complete. The solvent was evaporated to dryness and theresidue was used immediately for the next step.According to the general procedure, serinol 4 (49 mg, 0.54 mmol) was treated with the abovementioned arachidonic chloride (193 mg, 0.6 mmol) and TEA (0.1 mL) to give 182 mg (89%) of 9as an amorphous white solid. 1H NMR (400 MHz, DMSO-d6) 7.42 (d, J = 8.1 Hz, 1H, NHCO),5.34 (m, 8H, CH=), 4.54 (t, J = 5.6 Hz, 2H, OH), 3.68 (m, 1H, CHNH), 3.38 (t, J = 5.4 Hz, 4H, CH2OH),2.79 (m, 6H, CH2CH=), 2.08 (t, J = 7.5 Hz, 2H, CH2CO), 2.02 (m, 4H, CH2CH=), 1.53 (m, 2H, CH2),1.40-1.16 (m, 6H, CH2), 0.85 (t, J = 6.7 Hz, 3H, CH3). | |
With oxalyl dichloride In benzene at 0 - 20℃; | 1; 2A N,N-Di-3-chloro-4-hydroxybenzylarachadonamide (O-2093). To 212 mg (0.696 mmol) of arachadonic acid in 700 μL ahydrous benzene in a flame dried round bottom flask under nitrogen at 0° C. was added dropwise 121 μL oxalyl chloride (2 eq), followed by 1 drop anhydrous DMF. Copious gas evolved, and the reaction was stirred overnight at room temperature. The solvent was removed under vacuum and the residual oxalyl chloride removed by stripping with 3 mL anhydrous benzene then 1 mL anhydrous methylene chloride. The acid chloride was dissolved in 2 mL anhydrous methylene chloride and cannulated dropwise into 219 mg of di-(3-chloro-4-hydroxybenzyl)amine (1.1 eq) in 4 mL anhydrous THF at 0° C. under nitrogen. A white precipitate formed and the reaction was stirred 3 h at room temperature. The solids were removed by vacuum filtration and washed with 3×10 mL chloroform. 20 mL THF was added to the combined filtrate which was washed with 50 mL each 1 N HCl, saturated aqueous sodium bicarbonate, and brine, dried on sodium sulfate, and the solvent removed under vacuum. The crude product was plated on 1 g silica and purified by flash chromatography on 29 g silica, eluting with 49 hexanes/1 ethyl ether, then 4 hexanes/1 ethyl ether, then 2 hexanes/1 ethyl ether, then 1 hexanes/1 ethyl ether. This gave 162 mg (75% based on the amine) of the product as an off white wax.; 1H NMR (CDCl3) δ 7.0 (m, 6H), 6.1 (br s, 2H), 5.34 (m, 8H), 4.47 (d, 2H), 4.34 (d, 2H), 2.80 (m, 6H), 2.42 (t, 2H), 2.05 (m, 4H), 1.82 (m, 2H), 1.27 (m, 6H), 0.88 (t, 3H); Anal. Calc for C34H43NO3Cl2: C, 69.85, H, 7.41, N, 2.40, Cl, 12.13. Found: C, 69.96, H, 7.52, N, 2.31, Cl, 12.12. | |
With oxalyl dichloride In dichloromethane at 0 - 25℃; for 2h; | 1; 2B Eicosa-5,8,11,14-tetraenoic acid (4-chloro-benzyl)-(2,4-dichloro-benzyl)amide (O-2247). 4-Chlorobenzaldehyde (2 g, 14.23 mmol) was dissolved in 1,2-dichloroethane (65 mL) and acetic acid (0.82 mL, 14.23 mmol). 2,4-dichlorobenzylamine (2.8 g, 15.65 mmol) was added followed by sodium triacetoxyborohydride (4.8 g, 22.79 mmol). The mixture was stirred at 25° C. for two days. Separated layers with saturated NaHCO3 and EtOAc. The aqueous layer was extracted further with EtOAc. The combined organic layers were washed with brine, dried (MgSO4) and solvent removed. Purification by column chromatography (hexanes/EtOAc 9/1) gave 2.53 g (62%) of the desired secondary amine as a colorless oil. 1H NMR δ 1.68 (br.s, 1H), 3.76 (s, 2H), 3.84 (s, 2H), 7.21-7.41 (m, 7H). Arachidonic acid (213 mg, 0.69 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 0° C. Oxalyl chloride (134 μL, 1.54 mmol) was added dropwise followed by 2 drops of DMF. The ice bath was removed and the mixture stirred at 25° C. for 2 hours. The solvent was evaporated under vacuum. A solution of the acid chloride in CH2Cl2 (3 mL) was added to a solution of amine (1.0 g, 3.49 mmol) in CH2Cl2 (5 mL) at 0° C. The ice bath was removed and the mixture was stirred for two days at 25° C. It was diluted with CH2Cl2 and washed with 5% NaOH and brine. Dried (MgSO4) and removed solvent. The crude product was purified by column chromatography (hexanes/EtOAc 9/1 then 4/1) to give the desired product (O-2247) as a colorless oil (340 mg, 83%) in a 1:1 mixture of rotomers. 1H NMR δ 0.88 (t, 6H, 6.9 Hz), 1.23-1.41 (m, 12H), 1.79 (q, 4H, 6.9 Hz), 2.01-2.14 (m, 8H), 2.31 (t, 2H, 7.9 Hz), 2.41 (t, 2H, 7.9 Hz), 2.73-2.84 (m, 12H), 4.44 (br.s, 2H), 4.45 (br.s, 2H), 4.54 (br.s, 2H), 4.66 (br.s, 2H), 5.26-5.43 (m, 16H), 7.01-7.42 (m, 14H). Anal. Calcd for C34H42Cl3NO.0.5 C2H4Cl2.0.1 H2O: C, 66.04; H, 7.00. Found: C, 66.05; H, 6.80. | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1h; | EXAMPLE 26 (0390) (5 8ZJ lZJ4Z)-N-(3-(4-(trifluoromethyl)thiazol-2-yl)bicvclon. l . llpentan-l-yl)icosa- -tetraenamide (26) [0302] The following operations were performed in a manner as to minimize exposure to light. A solution of (5Z,8Z, l lZ, 14Z)-icosa-5,8, l l, 14-tetraenoic acid (40 mg, 0.131mmol) in DCM (0.9mL) and DMF (ΙOμ) was cooled to 0°C and oxalyl chloride (23μ1, 0.263mmol) was added dropwise. The reaction mixture was stirred for an additional lh followed by the addition of a solution of Compound 1 (107 mg, 0.394mmol) in pyridine (32μ1, 0.394mmol). The mixture was warmed to rt and stirred for an additional 30 minutes. The mixture was diluted with DCM (5mL) and washed with 10% aqueous HC1 and water. The organic layer was dried (Na2S04), concentrated and purified by flash chromatography (Si02, Hexanes/EtOAc) to provide 62 mg (91 %) of Compound 26 as a viscous pale yellow oil: lU NMR (400 MHz, CDC13) δ 7.65 (s, 1H), 5.86 (br s, 1H), 5.43-5.30 (m, 8 H), 2.86- 2.79 (m, 6H), 2.56 (s, 6 H), 2.18-2.03 (m, 6 H), 1.72 (quin, 7 =7.4 Hz, 2 H), 1.39- 1.24 (m, 6 H), 0.89 (t, 7=6.8 Hz, 3 H). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; | General procedure: To a solution of the opportune carboxylic acid (0.46 mmol) in dry CH2Cl2 (2 mL), oxalyl chloride (58 μL, 0.69 mmol) in dry CH2Cl2 (0.5 mL) was added dropwise at 0 °C under stirring. N,N-dimethylformamide (DMF, 1 drop) was added next. The reaction mixture was stirred at room temperature for 3 h and then concentrated under vacuum, giving crude acyl chloride. This residue was dissolved in dry CH2Cl2 (1 mL) and added dropwise to an ice-cold suspension of resorufin (50 mg, 0.23 mmol) and triethylamine (48 μL, 0.35 mmol) in dry CH2Cl2 (3 mL) and then stirred overnight at room temperature. After dilution with CH2Cl2 the salts residues were removed by filtration obtaining a brick-red solution; that was washed with 0.5 M HCl (2 mL) and saturated NaHCO3 (2.5 mL), dried on anhydrous Na2SO4 and concentrated to give the crude product that was purified with column chromatography on silica gel (Supplementary Table S1). Yields 62-92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In water; acetonitrile at 30℃; for 96h; | |
With potassium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | General procedure: To a stirred solution of the fatty acid (1.0 mmol, 1.0 equiv.) inCH2Cl2 (5 mL) was added CDI (0.178 g, 1.1 mmol, 1.1 equiv.).After 30 min at room temperature, the amine (1.1 mmol, 1.1equiv.) was added. After 12 h, CH2Cl2 (25 mL) was added, followedby saturated aqueous NH4Cl. The mixture was acidified topH 2 by addition of HCl, the organic phase was separated, andthe aqueous layer was further extracted with CH2Cl2 (3 × 10mL). The organic phases were combined, dried over Na2SO4, filtered,and concentrated in vacuo, to give the amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With diethyl cyanophosphonate; triethylamine In tetrahydrofuran for 1.5h; | |
79% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane; ethyl acetate at 0℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at -20 - 20℃; | |
29% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at -20 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at -20 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at -20 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at -20 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: ethanolamine In dichloromethane for 12h; | (21) General Procedure for Amide Coupling General procedure: To a stirred solution of the fatty acid (1.0 mmol, 1.0 equiv.) inCH2Cl2 (5 mL) was added CDI (0.178 g, 1.1 mmol, 1.1 equiv.).After 30 min at room temperature, the amine (1.1 mmol, 1.1equiv.) was added. After 12 h, CH2Cl2 (25 mL) was added, followedby saturated aqueous NH4Cl. The mixture was acidified topH 2 by addition of HCl, the organic phase was separated, andthe aqueous layer was further extracted with CH2Cl2 (3 × 10mL). The organic phases were combined, dried over Na2SO4, filtered,and concentrated in vacuo, to give the amide. |
85% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 20℃; for 0.166667h; Inert atmosphere; Stage #2: ethanolamine In dichloromethane; acetonitrile at 20℃; Inert atmosphere; | 2 2.3 Synthesis of NAEs (1a-1g) General procedure: These compounds were synthesized according to the procedure described previously with slight modifications (El-Faham and Albericio, 2010) The appropriate acid (0.15 mmol), (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluoro phosphate (COMU, 64.2 mg, 0.15 mmol), and DIPEA (0.05 ml, 0.30 mmol) were dissolved in anhydrous CH2Cl2 (0.5 ml) and CH3CN (2.5 ml) and the resulting orange-red solution was stirred at rt for 10 min under a nitrogen atmosphere. Ethanolamine (3) (0.15 mmol) in CH3CN (0.2 ml) was then injected into the reaction mixture and vigorous stirring at rt was continued until TLC (CH2Cl2/MeOH 98:2) confirmed the completion of the reaction (3-6 h). The reaction mixture was diluted with CH2Cl2 (3 ml) and the resulting mixture was washed with 5% HCl, saturated NaHCO3 and brine. The organic layer was collected, dried over anhydrous Na2SO4, filtered. The solvent was evaporated under reduced pressure and crude purified by flash chromatography. |
72.7% | With Candida antarctica lipase B In hexane at 50℃; for 6h; Inert atmosphere; Enzymatic reaction; |
64% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: ethanolamine In dichloromethane at 20℃; for 2h; Inert atmosphere; | |
With triethylamine; carbonochloridic acid, butyl ester In tetrahydrofuran; methanol; acetonitrile at 20℃; for 2h; | ||
Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With oxalyl dichloride; N,N-dimethyl-formamide In benzene at 0 - 20℃; for 1h; Stage #2: ethanolamine In tetrahydrofuran; benzene at 0 - 20℃; | A General Procedure A Chemical Synthesis of Arachidonyl Ethanolamide (Compound 2) The chemical synthesis of arachidonyl ethanolamide from arachidonic acid (Compound 1) is illustrated in Reaction Scheme 1. Arachidonyl ethanolamide (Compound 2) is synthesized following a literature procedure of Abadji et al., J. Med. Chem. 1994, 37, 1889-1893, incorporated herein by reference. To a 0.1 M solution of arachidonic acid (Compound 1, available from Cayman Chemical) in anhydrous benzene at 0° C. is added one equivalent of anhydrous dimethyl formamide and two equivalents of oxalyl chloride. The reaction is stirred at room temperature for 1 h and an equal volume of anhydrous tetrahydrofuran (THF) is added. The mixture is then cooled to 0° C. and a 1 M solution of 10 equivalents 2-amino-ethanol in anhydrous THF is added. The reaction is stirred at room temperature until completion. The reaction mixture is then diluted with chloroform, washed successively with 1 M HCl, 1 M NaOH, brine, dried over Na2SO4, and concentrated in vacuo. The crude product is purified by chromatography on silica gel. | |
With dmap; triethylamine; dicyclohexyl-carbodiimide | ||
With dmap; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 24h; | ||
3.8g | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With dmap; benzotriazol-1-ol In dichloromethane at 0 - 20℃; for 0.5h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 3h; Stage #3: ethanolamine at 20℃; for 16h; | 1 Example 1. (5Z,8Z,1 lZ,14Z)-N-(2-hydroxyethyl)icosa-5,8,11 ,14-tetraenamide (Compound 2; anandamide) To a stirred solution of arachidonic acid (Compound 1) (5 g, 1.64 mmol, 1.0 eq.) in CH2CI2 (100 mL) was added DMAP (2.0 g, 1.64 mmol, 1.0 eq.) and HOBT (1.1 g, 0.82 mmol, 0.5 eq.) in portion wise at room temperature. The reaction mixture was stirred at 0°C. After being stirred for 30 min, EDCI.HC1 (9.45 g, 4.93 mmol, 3.0 eq.) was added to the reaction mixture at 0°C; the mixture was then warmed to room temperature and continued stirring for 3 h. Next, ethanol amine (5.0 mL, 8.22 mmol, 5.0 eq.) was added dropwise and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was quenched with water (200 mL) and extracted with DCM (2 x 300 mL). The combined organic layer was washed with 2N HC1 (150 mL) followed by sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further purified by silica-gel column chromatography using ethyl acetate:hexane (15:85) as an eluent to afford anandamide (Compound 2) (3.8 g) as a light yellow colored liquid. [M+H]+ (m/z): 348.2; 1H-NMR (400 MHz, CDC13): d 5.94 (bs, 0.8 H), 5.44-5.30 (m, 8H), 3.73-3.71 (m, 2H), 3.44-3.35 (m, 2H), 2.85-2.79 (m, 6H), 2.22 (t, J = 7.6 Hz, 2H), 2.10-2.03 (m, 4H), 1.77-1.69 (m, 3H), 1.39-1.24 (m, 7H), 0.88 (t, J = 6.8 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 0.75h; Stage #2: (R)-4-hydroxyphenylglycinol hydrochloride With TEA In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2,4-Dimethoxybenzylamine In dichloromethane at 20℃; for 5h; Inert atmosphere; | Synthesis of AA-D2, AA-D4, AA-D6 Compounds. GeneralMethod General procedure: A solution of arachidonic acid 1 (100 mg, 0.33 mmol)and DCC (75 mg, 0.36 mmol) in anhydrous dichloromethane(4.2 mL) was stirred at room temperature for 30 min. Theappropriate amine 2 (1.0 equivalents, 0.50 mmol) in anhydrousdichloromethane (0.5 mL) was then added. The reactionmixture was further stirred at room temperature for 5h.After that, the solvent was removed under reduced pressureand the residue was purified by column chromatography onsilica gel (8/2 petroleum ether/ ethyl acetate as eluent) toafford the desired products in good yields. |
With TEA; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 0.75h; Stage #2: (2S)-2-amino-2-phenylethan-1-ol hydrochloride With TEA In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 0.75h; Stage #2: (S)-(+)-2-pyrrolidinemethanol hydrochloride With TEA In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 4-methoxy-benzylamine In dichloromethane at 20℃; for 5h; Inert atmosphere; | Synthesis of AA-D2, AA-D4, AA-D6 Compounds. GeneralMethod General procedure: A solution of arachidonic acid 1 (100 mg, 0.33 mmol)and DCC (75 mg, 0.36 mmol) in anhydrous dichloromethane(4.2 mL) was stirred at room temperature for 30 min. Theappropriate amine 2 (1.0 equivalents, 0.50 mmol) in anhydrousdichloromethane (0.5 mL) was then added. The reactionmixture was further stirred at room temperature for 5h.After that, the solvent was removed under reduced pressureand the residue was purified by column chromatography onsilica gel (8/2 petroleum ether/ ethyl acetate as eluent) toafford the desired products in good yields.(5Z, 8Z, 11Z, 14Z)-N-(4-methoxybenzyl)icosa-5,8,11,14-tetraenamide (AA-D2)Colorless oil (75% yield) 1H-NMR (300 MHz, CDCl3): 7.18 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 5.81 (bs,1H), 5.37-5.33 (m, 8H), 4.33 (d, J = 5.5 Hz, 2H), 3.77 (s,3H), 2.81-2.77 (m, 6H), 2.18 (t, J = 7.5 Hz, 2H), 2.15-2.00(m, 4 H), 1.77- 1.67 (q, J = 7.5 Hz, 2H), 1.34-1.24 (m, 6H),0.87 (t, J = 7.0 Hz, 3H); 13C-NMR (75 MHz, CDCl3):172.5, 158.9, 130.4, 129.1, 128.6, 128.5, 128.1, 127.7,127.4, 113.9, 55.2, 42.9, 35.9, 31.4, 29.2, 27.1, 26.6, 25.5,25.4, 22.5, 14.0. MS: m/z 423 (M+). Anal. calcd. forC28H41NO2: C, 79.39; H, 9.76; N, 3.31%; found: C, 79.37; H,9.73; N, 3.29%. |
With TEA; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Analog 5, N-(2-Chloroethyl)arachidonylamide. A solution of arachidonic acid (50 mg, 0.165 mmol) and 0.03 mL of anhydrous DMF in 1 mL of dry dichloromethane was cooled in an ice bath under argon and 0.17 mL of a 2 M solution of oxalyl chloride (0.34 mmol) in dichloromethane was added dropwise. Reaction mixture was stirred further at ice bath temperature for 1 hour. A solution of 65 mg (0.50 mmol, 3 equiv) of 2-chloroethylamine hydrochloride in 0.5 mL of dry pyridine was added, the cooling bath was removed, and the solution was stirred at room temperature for 30 min. The mixture was transferred to a separatory funnel, washed with 10% aqueous hydrochloric acid and water, and dried (MgSO4). After rotary evaporation of solvents, the residue was chromatographed on silica gel (60% ethyl ether-petroleum ether) to afford 54 mg (90%) of the pure title compound as an oil: Rf (70% ethyl ether-petroleum ether) 0.35; 1H NMR (270 MHZ, CDCl3) 5.80 (br s, 1H), 5.36 (m, 8H), 3.61 (m, 4H), 2.80 (m, 6H), 2.21 (t, J=7.89 Hz, 2H), 2.10 (m, 4H), 1.72 (m, 2H), 1.29 (m, 6H), 0.88 (t, J=6.79 Hz, 3H). Anal. (C22H36CINO) C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: diethyl ether 2: PtO2 / ethyl acetate / (hydrogenation) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol for 12 - 20h; | Ex: 0.05 m of proguanil hydrochloride and 0.05 m of arachidonic acid were refluxed in 250 ml of isopropanol for 12-20 hours. Upon evaporating off the solvent white crystals precipitated. Yields were about 90%. FTIR and nitrogen analysis confirmed it's structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; dichloromethane at 0℃; for 4h; | 4.3. 2-(Dodecanoyloxy)propane-1,3-diyl dibutyrate (2a) General procedure: EDCI (383 mg, 2.0 mmol), DMAP (19 mg, 0.16 mmol), and 1 (204 mg, 0.88 mmol) were added to a solution of lauric acid (160 mg, 0.80 mmol) in a 1:1 mixture of anhydrous THF/CH2Cl2 (10 mL) at 0 °C. The reaction mixture was allowed to stir for 4 h. The reaction mixture was then diluted with CH2Cl2 (15 mL) and H2O (15 mL). The organic layer was separated, dried over MgSO4, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel (0-15% ethyl acetate/hexanes) to yield 2a (221 mg, 67%) as a colorless oil. |
88% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h; | Preparation of 2 To a solution of 1,3-dibutanoylglyerol (1) (0.500 g, 2.45 mmol) and arachidonic acid (0.74 g, 2.45 mmol) in anhydrous dichloromethane (10 mL) was added DMAP (2.4 g, 19.6 mmol) and EDCI (1.88 g, 9.8 mmol). The resulting solution was stirred for 24 h. Cold water was added to the reaction mixture and washed with 5% HCl. The aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with water, brine, and dried over sodium sulfate. The reaction mixture was subjected to flash chromatography (hexanes/acetone; 7:3) to afford pure triglyceride as colorless oil (1.06 g, 88%). IR (neat) 3012, 2931, 1741, 1167, 1094 cm-1; 1H NMR (CDCl3, 500 MHz) δ 5.30-5.45 (m, 8H), 5.23-5.30 (m, 1H), 4.10-4.37 (m, 4H), 2.76-2.91 (m, 6H), 2.34 (t, J = 7.57 Hz, 2H), 2.30 (t, J = 7.57 Hz, 4H), 2.12 (q, J = 7.16 Hz, 2H), 2.06 (q, J = 7.32 Hz, 2H), 1.68-1.75 (m, 2H), 1.60-1.68 (m, 4H), 1.23-1.42 (m, 6H), 0.91-0.99 (m, 6H), 0.84-0.91 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 173.3, 172.8 (2C), 130.7, 129.2, 128.9, 128.8, 128.5, 128.3, 128.0, 127.7, 69.2, 62.3 (2C), 36.1 (2C), 33.8, 31.7, 29.5, 27.4, 26.7, 25.8 (3C), 24.9, 22.8, 18.5 (2C), 14.3, 13.8 (2C). |
72% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In all cis 5,8,11,14-eicosatetraenoic acid; ethyl acetate; | C:H:O Treated Dyneema Purity Braids with Arachidonic Acid and <strong>[3380-34-5]Triclosan</strong>: CHO-HPPE-A-TRI-2.0 Dyneema Purity braids (8*1*110) of Example 8 were further dip-coated for 10 min at 23 C. in a 6.0 g/L arachidonic acid solution in ethyl acetate containing 2.0 g/L <strong>[3380-34-5]triclosan</strong> (see Table 2). The resulting braids were dried at 23 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Candida antarctica B lipase In hexane at 55℃; for 1h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3,4-dimethoxybenzylamine In dichloromethane at 20℃; for 5h; Inert atmosphere; | Synthesis of AA-D2, AA-D4, AA-D6 Compounds. GeneralMethod General procedure: A solution of arachidonic acid 1 (100 mg, 0.33 mmol)and DCC (75 mg, 0.36 mmol) in anhydrous dichloromethane(4.2 mL) was stirred at room temperature for 30 min. Theappropriate amine 2 (1.0 equivalents, 0.50 mmol) in anhydrousdichloromethane (0.5 mL) was then added. The reactionmixture was further stirred at room temperature for 5h.After that, the solvent was removed under reduced pressureand the residue was purified by column chromatography onsilica gel (8/2 petroleum ether/ ethyl acetate as eluent) toafford the desired products in good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.0% | A solution of (5Z,8Z, l lZ,14Z)-icosa-5,8, l l, 14-tetraenoic acid (200 mg, 0.58 mmol) in DCM (4 ml) and DMF (0.12 ml) was cooled to 0 C and oxalyl chloride (0.116 ml, 1.31 mmol) was added dropwise. The reaction mixture was stirred for an additional 1 h followed by the addition of a solution of 8 (200 mg, 1.37 mmol) in pyridine (0.493 ml, 0.493 mmol). The mixture was warmed to rt and stirred for an additional 30 minutes. The mixture was diluted with DCM (5mL) and washed with 10% aq. HC1 and water. The organic layer was dried (Na2S04), concentrated and purified by flash Si02 chromatography (Hexanes/EtOAc) to provide 12 (30 mg, 12.0% yield) as a pale yellow oil: 1H NMR (400 MHz, CDC13) delta 8.11 (s, 1H), 7.68 (s, 1H), 7.54-7.56 (d, 1H), 7.41-7.43 (d, 1H), 5.75 (s, 1H), 5.31-5.40 (m, 9H), 4.55-4.56 (d, 2H), 2.79-2.82 (m, 6H), 2.22-2.57 (t, 2H),2.11-2.14 (m, 2H), 2.02-2.07 (m, 2H), 1.74-1.78 (m, 2H), 1.25-1.29 (m, 6H), 0.88 (t, J = 6.80 Hz, 3H); C28H39N30 Exact Mass: 433.31 EST m/z 456.2 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In water; acetonitrile at 37℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 14h; | 4.2.2. General experimental procedure for the synthesis of NHPI esters (5a-f) General procedure: The synthesis of NHPI esters (5a-g) followed Qin and coworkers [17] reported procedures with minor modification. Briefly, a round bottom flask (RBF) charged with PUFA (4, 1 eq.), 2- hydroxyisoindoline-1,3-dione (NHPI, 1 eq.), N, N-dimethylpyridin4-amine (DMAP, 0.1 eq.), diisopropylmethanediimine (DIC, 1 eq.) in dry dichloromethane (solvent, PUFA concentration 0.2 M) was stirred at room temperature for 14 h. The resulting mixture was concentrated in vacuo, and the residue was separated over preparative flash chromatography (SiO2, eluted with EtOAc: hexane 6 : 94 to 10 : 90), to yield the desired product as a colorless oil. |
With dmap; diisopropyl-carbodiimide In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: trifluoromethylsulfonic anhydride; 7-(diethylamino)-4-(hydroxymethyl)-2H-chromen-2-one With N-ethyl-N,N-diisopropylamine In dichloromethane for 0.0333333h; Inert atmosphere; Cooling with ice; Stage #2: all cis 5,8,11,14-eicosatetraenoic acid In dichloromethane; chloroform for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.8% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 43℃; for 3h; | 24 Example 24 Synthesis of AA-FK506 coupling prodrug, as shown in Figure 24: Add FK506 (120.6mg, 0.15mmol), arachidonic acid (45.7mg, 0.15mmol) and DMAP (18.3mg, 0.15mmol) in a 100mL round bottom flask, dissolve in 4mL of dry dichloromethane, and then drop quickly Add EDC (23.3mg, 0.15mmol). Stir at 43°C for 3 hours, and observe the reaction by thin layer chromatography.When the reaction is substantially completed, the reaction solution was cooled, respectively, with 0.1M hydrochloric acid solution, saturated sodium bicarbonate, and saturated brine; the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure and the filtrate collected; by column chromatography After chromatographic separation and purification (DCM:MeOH=40:1), product 24 (60.2mg, yield 36.8%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: all cis 5,8,11,14-eicosatetraenoic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-aminoethyl (2-(trimethylammonio)ethyl) phosphate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h; | 1 Example 1. Preparation of 2-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidoethyl 2- (trimethylammonio) ethylphosphate (Compound 3) To a stirred solution of (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoic acid (2.5 g, 8.22 mmol, 1.0 eq.) in dimethylformamide (DMF, 15 mL) was added 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 3.74 g, 9.86 mmol, 1.2 eq.) at room temperature. After stirring the reaction mixture for 30 minutes, N,N-Diisopropylethylamine (DIPEA, 4.29 mL, 24.6 mmol, 3.0 eq) was added followed by the addition of Intermediate 1 (2.78 g, 12.3 mmol, 1.5 eq) and the resulting mixture was stirred for about 18 hours at room temperature. The reaction mixture was diluted with isopropylether (IPE, 2 X 50 mL), cooled to 0°C, settled for 30 minutes, and the IPE layer was decanted (the diluting/decanting procedure was repeated a few times). The resulting residue was dried under vacuum. Isolated crude (8 g with 15% by LC-MS) was purified by PREP HPLC (Column: LUNA-C18, 250 X 21.2 mm, 1.6 pm; Mobile phase: [CH3CN: Water+0.01% HCOOH]; B%: 80%-50%, 22 min.; 50%-90%, 35 min) to yield Compound 3 (1.6 g) as a light brown sticky solid. Mass [m/z]: 513.2 [M+H]+. Yield: 1.6 g (38.0%). LC-MS Purity: 96.0% (LCMS Method A). HPLC Method: 90.3% (Analytical HPLC method). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With oxalyl dichloride; triethylamine In dichloromethane at 0 - 20℃; for 5h; | 3.6. Synthesis of 2-((5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoyloxy)propane-1,3-diyl dibenzoate (2) To a solution of arachidonic acid (110 mg, 0.37 mmol) and Et3N (1 eq) in anhydrousDCM (3 mL), cooled by an ice bath, oxalylchloride (2 eq) was slowly added and the reactionmixture stirred for 5h. The obtained chloride was then reacted with 1,3-dibenzoylglycerol(1) (75 mg, 0.37 mmol), without further purification, in anhydrous DCM containing Et3N(0.07 mL, 0.5 mmol) and the solution was stirred for 24 h. The solvent was then evaporatedand crude was purified by flash chromatography (hexane/acetone; 7:3) to afford puretriglyceride as colorless oil (1.06 g, 85%). Rf 0,64 (hexane/acetone; 7:3). IR (neat) 3012, 2931,1741, 1456, 1167, 1094 cm1; 1H NMR (CDCl3) 8.06 (4H, d, J = 7.8 Hz, Hortho), 7.57 (2H, t,J = 7.8 Hz, Hpara), 7.45 (4H, d, J = 7.8 Hz, Hmeta), 5.54-5.48 (m, 1H, 2-CH), 5.32-5.50 (8H,m, 50- 60- 80- 90- 110- 120- 140- 150-CH), 4.75-4.45 (4H, m, 1 and 3-CH2), 2.82-2.88 (6H, m, 70-100- and 130-CH2), 2.64 (2H, t, J = 7.0, 20-CH2), 2.24 (2H, dt, J = 7.0, 7.4, 40-CH2), 2.08 (2H, dt,J = 7.6, 7.6, 160-CH2), 1.87 (2H, tt, J = 7.0, 7.6, 30-CH2), 1.28-1.39 (6 H, m, 170-, 180-, 190-CH2),0.90 (3H, t, J = 7.6, 200-CH3); 13C NMR (CDCl3) 172.8 (10-CO), 166.1 (CO), 133.3, 130.5,129.7, 129.5, 129.5, 128.7, 128.5, 128.3, 128.0, 127.8, 127.5 (50, 60, 80, 90, 110, 120, 140, 150, Cpara,Cortho, Cmeta), 69.1 (2-CH), 62.3 (1 and 3-CH2), 33.7 (20), 31.5 (180), 29.3 (170), 27.2 (160), 26.5(40), 25.6 (70, 100, 130), 24.7 (30), 22.6 (190), 14.1 (200). |
Tags: 506-32-1 synthesis path| 506-32-1 SDS| 506-32-1 COA| 506-32-1 purity| 506-32-1 application| 506-32-1 NMR| 506-32-1 COA| 506-32-1 structure
A344981[ 69254-37-1 ]
5Z,8z,11z,14z-eicosatetraenoic-5,6,8,9,11,12,14,15-d8acid
Reason: Stable Isotope
[ 28845-86-5 ]
(13Z,16Z,19Z)-Docosa-13,16,19-trienoic acid
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[ 111219-92-2 ]
(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14,19-pentaenoic acid
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[ 29204-16-8 ]
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