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CAS No. : | 5675-51-4 | MDL No. : | MFCD00004755 |
Formula : | C12H26O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GHLKSLMMWAKNBM-UHFFFAOYSA-N |
M.W : | 202.33 | Pubchem ID : | 79758 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 11 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 62.12 |
TPSA : | 40.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.65 cm/s |
Log Po/w (iLOGP) : | 3.06 |
Log Po/w (XLOGP3) : | 4.06 |
Log Po/w (WLOGP) : | 2.87 |
Log Po/w (MLOGP) : | 2.49 |
Log Po/w (SILICOS-IT) : | 3.35 |
Consensus Log Po/w : | 3.17 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.93 |
Solubility : | 0.24 mg/ml ; 0.00119 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.61 |
Solubility : | 0.00492 mg/ml ; 0.0000243 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -3.59 |
Solubility : | 0.0516 mg/ml ; 0.000255 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 1.89 |
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 |
---|---|---|
87% | With hydrogen bromide In water; toluene for 48 h; Inert atmosphere; Reflux | To a solution of diol 7 (28 g, 0.14 mol) in toluene (600 mL) was added concentrated HBr [27.5 mL of a 48percent (9 M) aqueous solution, 0.162 mol]. The heterogeneous mixture was heated at reflux for 36 h, after which TLC analysis showed that 20percent of the diol still remained. Thus, a further quantity of HBr (10 mL, 0.09 mol) was added, and the mixture was heated at reflux for a further 12 h, after which TLC analysis showed no diol remaining. The reaction mixture was allowed to return to room temperature, and the phases were separated. The organic layer was diluted with ether (200 mL) and washed with 1 M NaOH solution (200 mL) and brine solution (300 mL). Drying over anhydrous Na2SO4, filtration and concentration of the organic layer gave a yellow oil, which was purified by column chromatography using hexane/ether as eluent (7:3) to provide 8 as a pale yellow oil (32.0 g, 87percent). 1H NMR (300 MHz, CDCl3): δ 3.64 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H), 1.89-1.80 (m, 2H), 1.61-1.51 (m, 2H), 1.44-1.27 (m, 16H); 13C NMR (75 MHz, CDCl3): δ 62.8, 33.9, 32.7, 32.6, 29.5, 29.4, 29.3, 28.7, 28.1, 25.6; IR (neat): 3358, 2923, 2362,1740,1515,1052 cm-1; ESI-MS: m/z 365 (M+H)+. |
85% | With hydrogen bromide In cyclohexane; water for 6 h; Reflux | Example 1 Preparation of 12-bromododecan-1-ol (3) 48percent HBr in water (77 ml; 0.46 mol; 15 eq.) is added to a solution of 1,12-dodecan-ol (6.15 g; 30.4 mmol; 1 eq.) in cyclohexane (140 ml). The heterogeneous mixture is heated under reflux. After 6 h, the aqueous phase is extracted with ether (3*100 ml). The organic phases are combined, washed with a saturated solution of Na2CO3, dried on MgSO4, filtered and evaporated. The crude reaction product is purified by silica gel chromatography (eluent: hexane-AcOEt: 6-4) to yield 7.06 g of a white solid. Yield: 85percent Empirical formula: C12H25BrO |
85% | With hydrogen bromide In water; toluene for 48 h; Reflux | To a solution of 1,12-dodecanediol (1.00 g, 4.94 mmol) in toluene (20 mL) was added aqueous HBr (48percent, 0.67 mL, 5.33 mmol) and the resulting mixture was refluxed until the diol was completely consumed by TLC monitoring (48 h). The mixture was cooled to room temperature and quenched with 1M NaOH. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with H2O and brine, dried over MgSO4, and evaporated. The resulting residue was purified by column chromatography (SiO2, hexane/EtOAc 3:1) to furnish S1 (1.11 g, 85percent) as a pale yellow oil |
78% | With hydrogen bromide In water; toluene for 3 h; Reflux | To a stirred solution of dodecane-1,12-diol (8.365 g, 42.75 mmol), 48percent HBr in water (9.7 ml, 85.50 mmol) and toluene (120 ml) were added and the reaction mixture refluxed for 3 h. The reaction mixture was then concentrated, the crude compound was dissolved in DCM (150 ml), washed with water, NaHCO3 brine solution, dried over MgSO4 and concentrated. The crude product was purified by silica gel column (5percent EtOAc in hexane) to obtain 12-bromododecan-1-ol as an off-white low melting solid (8.87 g, 78percent). Rf=0.55 (10percent EtOAc in Hexane, KMnO4 active.). 1H NMR (300 MHz, CDCl3) δ 3.63 (t, 2H), 3.40 (t, 2H), 3.85 (m, 2H), 1.59-1.51 (m, 2H), 1.44-1.27 (m, 16H); 13C NMR (75 MHz, CDCl3) δ 62.91, 34.00, 32.82, 32.74, 29.56, 29.50, 29.41, 29.22, 28.74, 28.15, 25.73; MS (EI) m/z 220 (3.6percent), 164 (8.7percent), 162 (8.1percent), 150 (13.7percent), 148 (13.6percent), 97 (31.9percent), 83 (45.4percent), 82 (58.7percent), 69 (66.7percent), 68 (54.2percent), 55 (100percent), 41 (57.9percent); HRMS Calculated: 264.1089. Found: [M-18]+=246.09741. |
73% | With hydrogen bromide In cyclohexane; water for 6 h; Heating / reflux | Synthesis Example B-(10) 1,10-Dodecanediol (2 g) was dissolved in 25 ml of cyclohexane, and 57percent hydrobromic acid solution (25 ml) was added to this solution. The reaction mixture was refluxed for six hours while stirring. After the reaction, the mixture was extracted three times with diethyl ether. The organic layer was neutralized with saturated sodium hydrogen carbonate solution, washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane: ethyl acetate = 7:3) gave 12-bromododecan-1-ol as white crystals at a 73percent yield. Molecular weight: 265.23 (C12H25BrO) TLC: (hexane-ethyl acetate 7-3) Rf value=0.53 1H-NMR: (300MHz, CDCl3) δ:1.26 (s large, 16H, -(CH2)6-); 1.56 (qt, 2H, J=6.9Hz, -CH2-); 1.85 (qt, 2H, J=7.1Hz, -CH2-); 3.40 (t, 2H, J=7.1Hz, -CH2-Br); 3.64 (t, 2H, J=6.6Hz, -CH2-O-) 13C-NMR: (75MHz; CDCl3)δ: 25.72; 27.28; 28.16; 28.74; 29.40; 29.49; 29.55; 30.92; 32.79; 32.82; 34.05; 63.08 |
65% | With hydrogen bromide In toluene at 110℃; for 24 h; | General procedure: To a stirred solution of 1,6-hexanodiol 1a (1.00 equiv.), 1,9-nonanediol 1b (1.00 equiv.), or 1,12-dodecanediol 1c (1.00 equiv.), in 30 mL of toluene was added HBr 48 percent (2.00 equiv.). The reaction was stirred at 110 °C for 24 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography over silica gel, eluting with hexane/EtOAc 9:1, to yield pure haloalcohol 2a–c. These compounds were transformed into their corresponding azido alcohols 3a–c by SN2 substitution (Scheme 1). A stock solution of 0.5 M NaN3 in DMSO was prepared by stirring the solution for 24 h at room temperature. To a 100-mL round-bottom flask equipped with a magnetic stir bar was added a 0.5 M solution of NaN3 in DMSO at room temperature. To this solution was added the bromo alcohol 2a (1.00 equiv.), 2b (1.00 equiv.), or 2c (1.00 equiv.), and the mixture was stirred for 24 h at room temperature.The reaction was quenched with H2O (50 mL) and stirred until it cooled to room temperature. The mixture was extracted with Et2O (3 9 30 mL), and the resulting extracts were washed with H2O (3 x 50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and filtered, and the residue obtained was purified by column chromatography over silica gel, eluting with hexane/EtOAc 9:1, to yield pure alkyl azido alcohols 3a–c. A solution of the azido alcohol 3a (1.00 equiv.), 3b (1.00 equiv.), or 3c (1.00 equiv.) in CH2Cl2 (50 mL) was cooled to 0 °C. Et3N (2.00 equiv.) and methanesulfonyl chloride (2.00 equiv.) was added. The reaction mixture was stirred for 24 h and then allowed to reach room temperature. The reaction mixture was poured into crushed ice (70 mL) and was then extracted with methylene chloride (3 9 30 mL). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue obtained was purified by column chromatography over silica gel, eluting with hexane/EtOAc 9:1, to yield highly purified halo alcohol pure methanesulfonate alkyl azides compounds 4a, 4b, and 4d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.5% | With hydrogen In ethanol at 220℃; for 10h; | |
94.5% | With lithium aluminium tetrahydride In diethyl ether; benzene for 6h; Heating; | |
With ethanol; sodium |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogenchloride In n-heptane at 95 - 100℃; for 12h; Heating; | |
80% | With hydrogenchloride In n-heptane at 95 - 100℃; for 25h; during the reaction was product continuously extracted with heptane; | |
48% | With tetrachloromethane at 120℃; for 8h; |
With hydrogenchloride at 95℃; unter Extraktion mit Benzin; | ||
With hydrogenchloride; copper(l) chloride | ||
With hydrogenchloride In Petroleum ether for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus; iodine at 150℃; | ||
With phosphoric acid; potassium iodide | ||
With hydrogen iodide for 2h; Heating; |
With N-iodo-succinimide; triphenylphosphine In dichloromethane at 20℃; for 10h; | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 5 h / 0 °C 2: sodium iodide / acetone / 16 h | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 6 h / 0 - 20 °C 2: sodium iodide / acetone / 12 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With hydrogen bromide In benzene for 20h; Heating; | |
88% | With hydrogen bromide In benzene for 28h; Heating; | |
87% | With hydrogen bromide In water; toluene for 48h; Inert atmosphere; Reflux; | 4.1.1. 12-Bromododecan-1-ol 8 To a solution of diol 7 (28 g, 0.14 mol) in toluene (600 mL) was added concentrated HBr [27.5 mL of a 48% (9 M) aqueous solution, 0.162 mol]. The heterogeneous mixture was heated at reflux for 36 h, after which TLC analysis showed that 20% of the diol still remained. Thus, a further quantity of HBr (10 mL, 0.09 mol) was added, and the mixture was heated at reflux for a further 12 h, after which TLC analysis showed no diol remaining. The reaction mixture was allowed to return to room temperature, and the phases were separated. The organic layer was diluted with ether (200 mL) and washed with 1 M NaOH solution (200 mL) and brine solution (300 mL). Drying over anhydrous Na2SO4, filtration and concentration of the organic layer gave a yellow oil, which was purified by column chromatography using hexane/ether as eluent (7:3) to provide 8 as a pale yellow oil (32.0 g, 87%). 1H NMR (300 MHz, CDCl3): δ 3.64 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H), 1.89-1.80 (m, 2H), 1.61-1.51 (m, 2H), 1.44-1.27 (m, 16H); 13C NMR (75 MHz, CDCl3): δ 62.8, 33.9, 32.7, 32.6, 29.5, 29.4, 29.3, 28.7, 28.1, 25.6; IR (neat): 3358, 2923, 2362,1740,1515,1052 cm-1; ESI-MS: m/z 365 (M+H)+. |
87% | With hydrogen bromide In water; toluene at 110℃; for 24h; | |
85% | With hydrogen bromide at 80 - 90℃; for 12h; darkness; | |
85% | With hydrogen bromide In cyclohexane; water for 6h; Reflux; | 1 Example 1 Preparation of 12-bromododecan-1-ol (3) 48% HBr in water (77 ml; 0.46 mol; 15 eq.) is added to a solution of 1,12-dodecan-ol (6.15 g; 30.4 mmol; 1 eq.) in cyclohexane (140 ml). The heterogeneous mixture is heated under reflux. After 6 h, the aqueous phase is extracted with ether (3*100 ml). The organic phases are combined, washed with a saturated solution of Na2CO3, dried on MgSO4, filtered and evaporated. The crude reaction product is purified by silica gel chromatography (eluent: hexane-AcOEt: 6-4) to yield 7.06 g of a white solid. Yield: 85% Empirical formula: C12H25BrO |
85% | With hydrogen bromide In water; toluene for 48h; Reflux; | 12-Bromododecan-1-ol (S1) To a solution of 1,12-dodecanediol (1.00 g, 4.94 mmol) in toluene (20 mL) was added aqueous HBr (48%, 0.67 mL, 5.33 mmol) and the resulting mixture was refluxed until the diol was completely consumed by TLC monitoring (48 h). The mixture was cooled to room temperature and quenched with 1M NaOH. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with H2O and brine, dried over MgSO4, and evaporated. The resulting residue was purified by column chromatography (SiO2, hexane/EtOAc 3:1) to furnish S1 (1.11 g, 85%) as a pale yellow oil |
83% | With hydrogen bromide In water; toluene at 120℃; for 16h; | 12-bromododecan-1-ol (2a). Yield 83%, brown oil. In a solutionof dodecane-1,12-diol (1a) (5.74 mmol) in Toluene (30 mL), wasadded aqueous hydrobromic acid 48% (6.31 mmol). The mixturewas heated at 120 C for 16 h. This mixturewas allowed to cool, andthe solvent was removed under reduced pressure. The residueobtained was chromatographed on silica gel using with hexane/ethyl acetate (8:2 v/v) as the eluent to yield the pure compound 2a.FT-IR (KBr) n/cm1 3358 (-OH), 2924 (eCH2e), 2852 (eCH2e), 1456(eCH2e), 1056 (-C-O-), 721 (eCH2e), 646 (-C-Br). 1H RMN(400 MHz, CDCl3) d ppm: 1.29e1.47 (m, 16H, 8 CH2), 1.56 (quintJ 6.8 Hz, 2H, -CH2-CH2-Br), 1.83 (quint, J 6.9 Hz, 2H, -CH2-CH2-OH), 3.40 (t, J 6.7 Hz, 2H, -CH2-Br), 3.63 (t, J 6.8 Hz, 2H, -CH2-OH). 13C RMN (100 MHz, CDCl3) d ppm: 25.73, 28.18, 28.76, 29.41,29.58, 32.80 (10 CH2), 34.06 (-CH2-Br), 63.06 (-CH2-OH). |
82% | With hydrogen bromide In water; toluene for 65h; Reflux; | |
80% | With hydrogen bromide In toluene for 18h; Heating; | |
80% | With hydrogen bromide In water; toluene for 18h; Dean-Stark; Reflux; | |
78% | With hydrogen bromide In water; toluene for 3h; Reflux; | 8.a (a) Synthesis of 12-bromododecan-1-ol To a stirred solution of dodecane-1,12-diol (8.365 g, 42.75 mmol), 48% HBr in water (9.7 ml, 85.50 mmol) and toluene (120 ml) were added and the reaction mixture refluxed for 3 h. The reaction mixture was then concentrated, the crude compound was dissolved in DCM (150 ml), washed with water, NaHCO3 brine solution, dried over MgSO4 and concentrated. The crude product was purified by silica gel column (5% EtOAc in hexane) to obtain 12-bromododecan-1-ol as an off-white low melting solid (8.87 g, 78%). Rf=0.55 (10% EtOAc in Hexane, KMnO4 active.). 1H NMR (300 MHz, CDCl3) δ 3.63 (t, 2H), 3.40 (t, 2H), 3.85 (m, 2H), 1.59-1.51 (m, 2H), 1.44-1.27 (m, 16H); 13C NMR (75 MHz, CDCl3) δ 62.91, 34.00, 32.82, 32.74, 29.56, 29.50, 29.41, 29.22, 28.74, 28.15, 25.73; MS (EI) m/z 220 (3.6%), 164 (8.7%), 162 (8.1%), 150 (13.7%), 148 (13.6%), 97 (31.9%), 83 (45.4%), 82 (58.7%), 69 (66.7%), 68 (54.2%), 55 (100%), 41 (57.9%); HRMS Calculated: 264.1089. Found: [M-18]+=246.09741. |
77% | With hydrogen bromide In water; toluene for 24h; Reflux; | |
77% | With hydrogen bromide In cyclohexane; water for 18h; Reflux; | |
76% | With hydrogen bromide In water; toluene for 1h; Reflux; Microwave irradiation; | |
75% | With hydrogen bromide In n-heptane Heating; | |
75% | With hydrogen bromide In benzene 1.) 60 deg C, 30 min, 2.) 90 deg C, 4 h; | |
75% | With hydrogen bromide In toluene | |
74% | With hydrogen bromide | |
73% | With hydrogen bromide In cyclohexane; water for 6h; Heating / reflux; | B-10 Synthesis Example B-(10) 1,10-Dodecanediol (2 g) was dissolved in 25 ml of cyclohexane, and 57% hydrobromic acid solution (25 ml) was added to this solution. The reaction mixture was refluxed for six hours while stirring. After the reaction, the mixture was extracted three times with diethyl ether. The organic layer was neutralized with saturated sodium hydrogen carbonate solution, washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane: ethyl acetate = 7:3) gave 12-bromododecan-1-ol as white crystals at a 73% yield. Molecular weight: 265.23 (C12H25BrO) TLC: (hexane-ethyl acetate 7-3) Rf value=0.53 1H-NMR: (300MHz, CDCl3) δ:1.26 (s large, 16H, -(CH2)6-); 1.56 (qt, 2H, J=6.9Hz, -CH2-); 1.85 (qt, 2H, J=7.1Hz, -CH2-); 3.40 (t, 2H, J=7.1Hz, -CH2-Br); 3.64 (t, 2H, J=6.6Hz, -CH2-O-) 13C-NMR: (75MHz; CDCl3)δ: 25.72; 27.28; 28.16; 28.74; 29.40; 29.49; 29.55; 30.92; 32.79; 32.82; 34.05; 63.08 |
70% | With hydrogen bromide In n-heptane for 25h; Heating; | |
70% | With hydrogen bromide In water; toluene Reflux; | |
69% | With hydrogen bromide In toluene Reflux; | |
65% | With hydrogen bromide In water | |
65% | With hydrogen bromide In toluene at 110℃; for 24h; | General procedure for the synthesis of methanesulfonatealkylazides (4a, 4b, and 4d) General procedure: To a stirred solution of 1,6-hexanodiol 1a (1.00 equiv.), 1,9-nonanediol 1b (1.00 equiv.), or 1,12-dodecanediol 1c (1.00 equiv.), in 30 mL of toluene was added HBr 48 % (2.00 equiv.). The reaction was stirred at 110 °C for 24 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography over silica gel, eluting with hexane/EtOAc 9:1, to yield pure haloalcohol 2a-c. These compounds were transformed into their corresponding azido alcohols 3a-c by SN2 substitution (Scheme 1). A stock solution of 0.5 M NaN3 in DMSO was prepared by stirring the solution for 24 h at room temperature. To a 100-mL round-bottom flask equipped with a magnetic stir bar was added a 0.5 M solution of NaN3 in DMSO at room temperature. To this solution was added the bromo alcohol 2a (1.00 equiv.), 2b (1.00 equiv.), or 2c (1.00 equiv.), and the mixture was stirred for 24 h at room temperature.The reaction was quenched with H2O (50 mL) and stirred until it cooled to room temperature. The mixture was extracted with Et2O (3 9 30 mL), and the resulting extracts were washed with H2O (3 x 50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and filtered, and the residue obtained was purified by column chromatography over silica gel, eluting with hexane/EtOAc 9:1, to yield pure alkyl azido alcohols 3a-c. A solution of the azido alcohol 3a (1.00 equiv.), 3b (1.00 equiv.), or 3c (1.00 equiv.) in CH2Cl2 (50 mL) was cooled to 0 °C. Et3N (2.00 equiv.) and methanesulfonyl chloride (2.00 equiv.) was added. The reaction mixture was stirred for 24 h and then allowed to reach room temperature. The reaction mixture was poured into crushed ice (70 mL) and was then extracted with methylene chloride (3 9 30 mL). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue obtained was purified by column chromatography over silica gel, eluting with hexane/EtOAc 9:1, to yield highly purified halo alcohol pure methanesulfonate alkyl azides compounds 4a, 4b, and 4d. |
65% | With hydrogen bromide In cyclohexane; water for 6h; Reflux; | |
64% | With hydrogen bromide In benzene for 24h; Heating; | |
60% | With hydrogen bromide In toluene for 16h; Heating; | |
56% | With hydrogen bromide In toluene at 60℃; for 24h; | |
56% | With hydrogen bromide In water; toluene at 60℃; for 24h; | |
54% | With hydrogen bromide | |
53.5% | With hydrogen bromide In water; toluene at 120℃; for 48h; Inert atmosphere; | |
51% | With tetrabutylammomium bromide; hydrogen bromide for 0.0666667h; Microwave irradiation; | |
50% | With carbon tetrabromide; triphenylphosphine | |
45% | With carbon tetrabromide; triphenylphosphine In tetrahydrofuran for 0.5h; Ambient temperature; | |
39% | With hydrogen bromide In water for 1h; Reflux; | |
38% | With carbon tetrabromide; triphenylphosphine In tetrahydrofuran for 20h; Ambient temperature; | |
With diethyl ether; hydrogen bromide | ||
With hydrogen bromide | ||
With hydrogen bromide | ||
With hydrogen bromide In benzene | ||
With hydrogen bromide In toluene Heating; | ||
With hydrogen bromide In octane | ||
With hydrogen bromide In n-heptane Heating; | ||
With hydrogen bromide In cyclohexane for 6h; Heating; | ||
With hydrogen bromide In cyclohexane for 6h; Heating; | ||
With hydrogen bromide In benzene Heating; | ||
With hydrogen bromide In toluene | ||
In hydrogen bromide | 1 12-Bromododecan-1-ol EXAMPLE 1 12-Bromododecan-1-ol 1,12-Dodecanediol (50 g, 0.25 mol) in hydrogen bromide 48% (220 ml) was continuously extracted with petroleum ether (b.p. 80-100° C.) (300 ml) for 18 hours. The solvent was evaporated under reduced pressure and the crude oil obtained was filtered through a pad of silica gel. Elution with petroleum ether (b.p. 40-60° C.) gave a colourless fraction containing 1,12-dibromododecane. The silica gel was then eluted with acetone to give the title compound as a pale yellow oil after evaporation of the solvent. The title compound crystallized upon cooling and was recrystallized from petroleum ether (b.p. 40-60° C.). 1H NMR (60 MHz; CDCl3): 3.62 (t, 2H), 3.42 (t, 2H), 1.4 (brs, 21H). | |
With hydrogen bromide In water; toluene Reflux; | ||
With hydrogen bromide In toluene at 110℃; for 32h; | ||
With hydrogen bromide In toluene for 16h; Reflux; | ||
With hydrogen bromide Inert atmosphere; | ||
With hydrogen bromide In water; toluene for 48h; Reflux; | ||
With hydrogen bromide In toluene at 110℃; for 24h; | 2.2.2. Synthesis of 1,2,3-alkyltriazoles 10 and 11 General procedure: Synthesis of 1,2,3-alkyltriazoles 10 and 11 To a stirred solution of the 1,12-dodecanediol (5) (1.00 equiv) in 30 mL of toluene HBr 48% (2.00 equiv) was added. The reaction was stirred at 110 °C for 24 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography over silica gel, eluting with hexane/EtOAc 9:1, to yield pure halo alcohol (6). | |
With hydrogen bromide In toluene for 75h; Reflux; | ||
With hydrogen bromide In toluene Reflux; Inert atmosphere; | ||
With hydrogen bromide In toluene at 120℃; for 16h; | 4.1.2. General Synthesis Procedure for Bromoalcohols 8a, 8b,and 8c. General procedure: To a stirred solution of diol 7 (300 mmol, 1.0 equiv)in toluene (600 mL) was added slowly 48% HBr (360 mmol,1.2 equiv) at RT. -e reaction mixture was reLuxed at 120°Cfor 16 h. After cooling to 0°C for 30 min, the organic layerwas separated and washed with saturated NaHCO3 solution.-e resulting aqueous layer was extracted with hexane(120 mL× 3). -e combined organic layer was washed withbrine (300 mL), dried over anhydrous MgSO4, :ltered, andconcentrated in vacuo to obtain the corresponding bromoalcohol8 as a light yellow oil. -e crude bromoalcohol 8was employed in the next step without further puri:cation.Bromoalcohols 8a, 8b, and 8c were synthesized independentlyaccording to the general procedure with 90%, 85%,and 91% yields, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hydrogen sulfate In hexane; water; dimethyl sulfoxide at 40℃; for 16h; | General procedure for the synthesis of monotetrahydropyranyl acetals 2a-d General procedure: A mixture of 1,n-diols 1a-d (1.0 mmol), DHP-hexane 3% (v/v) (1.96 mmol) and aqueous 5 M NaHSO4 (01 mL) was prepared. To 1,10-decanediol 1c and 1,12-dodecanediol 1d, 0.2 mL of DMSO were also added to the mixture at the beginning of the reaction. This mixture was stirred at 40 °C for 16 h and then extracted with hexane (3 × 20 mL). The combined organic phases were dried (Na2SO4), filtered and then evaporated under reduced pressure. The residue obtained was chromatographed using silica gel using hexane/EtOAc (8:2) to yield pure Compounds 2a-d. |
67% | With toluene-4-sulfonic acid In tetrahydrofuran; dichloromethane | |
55% | With pyridinium p-toluenesulfonate In tetrahydrofuran at 60℃; |
54% | With iodine In dichloromethane | |
52% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 0.5h; | |
With toluene-4-sulfonic acid In dichloromethane | ||
In tetrahydrofuran; dichloromethane | 287.1 (1) (1) 12-(Tetrahydropyran-2-yloxy)dodecanol 1,12-Dodecanediol (25 g) was dissolved in dichloromethane (200 ml) and tetrahydrofuran (200 ml), and a catalytic amount of p-toluenesulfonic acid and 3,4-dihydro-2H-pyran (14 ml) were added thereto. The mixture was allowed to stand at room temperature for 2 hours and the reaction was stopped by triethylamine. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:2) to give the subject compound (15.46 g) as a colorless, oily substance. Rf value: 0.39 (ethyl acetate:hexane=1:2); 1 H-NMR (CDCl3 /TMS) δ: 1.28 (16H, m), 1.62 (10H, m), 3.65 (6H, m), 4.59 (1H, br.s); IR(neat): 3417, 2927, 2854, 1034 cm-1; MS(EI): 285 (M+ -1). | |
With sodium hydrogen sulfate In hexane; dimethyl sulfoxide at 40℃; for 16h; | ||
In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; | 22.1 Step 1; A solution of DHP (13.9 g, 165 mmol) in 10 mL of THF was added to a reaction flask containing a solution of 1,12-dodecanediol (50.0 g, 247 mmol) and a catalytic amount of PPTS in anhydrous THF (100 mL). The reaction mixture was stirred under N2 at room temperature for 24 h and then poured into sodium bicarbonate saturated water. The organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic solution was dried over anhydrous magnesium sulfate, concentrated and purified with flash chromatography to give 24.8 g of product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N,N-diethyl-α,α-difluorobenzylamine In n-heptane for 0.166667h; Heating; microwave irradiation; | |
91% | With N,N-diethyl-α,α-difluoro-(meta-methylbenzyl)amine In n-heptane for 0.166667h; microwave irradiation; | |
71% | With 4 A molecular sieve; p-toluenesulfonyl fluoride; tetrabutyl ammonium fluoride In tetrahydrofuran for 17h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 1-hexadecylcarboxylic acid; stearic acid at 350℃; | |
With scandium(III) oxide In ethanol at 400℃; for 5h; Inert atmosphere; | ||
Multi-step reaction with 4 steps 1: hydrogen bromide / water; toluene / 48 h / Inert atmosphere; Reflux 2: 1H-imidazole / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 3: potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 4: toluene-4-sulfonic acid / methanol / 1 h / 0 - 20 °C / Inert atmosphere |
With indium(III) oxide at 500℃; for 1h; Inert atmosphere; | 18 11-Dodecen-1-ol: [0301j 11-Dodecen-1-ol: Monodehydration of 1,12-dodecanediol to 11-dodecen-1-ol is carried out according to a vapor-phase catalytic process as described in M. Segawa et al. Journal of Molecular Catalysis A: Chemical 2009, 310, 166. The catalytic reactions are performed in a fixed-bed down-flow reactor with the inside diameter of 17 mm. Prior to the reactions, an 1n203 sample (weight, W= 0.50 g) is preheated in the reactor in N2 flow at 500°C for 1 h. The temperature of catalyst bed set at a prescribed temperature between 300 and375 oC, and 1,12-dodecanediol is then fed through the reactor top at a liquid feed rate of 2.67 mL per hour together with N2 flow of 30 mL per mm. The effluent is collected at -77 °C, analyzed by GC. The 11-dodecen-1-ol product is purified by distillation. | |
Multi-step reaction with 3 steps 1: hydrogen bromide / toluene / Reflux; Inert atmosphere 2: sodium iodide / acetone / Inert atmosphere; Molecular sieve; Reflux 3: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.33 h / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With air; sodium nitrite In trifluoroacetic acid at 0 - 20℃; for 5h; | |
58% | With hydrogenchloride; calcium hypochlorite In tetrachloromethane; <i>tert</i>-butyl alcohol for 7h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide for 4h; | |
86% | With 1-methyl-1H-imidazole; [2,2]bipyridinyl; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; tetrakis(acetonitrile)copper(I)tetrafluoroborate In acetonitrile at 20℃; for 72h; Inert atmosphere; | |
86% | With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 2h; |
85% | With 4-hydroxy-TEMPO benzoate; sodium bromide In dichloromethane; water NaHCO3-buffered at pH 8.6; electrolysis; | |
66% | With pyridinium chlorochromate In dichloromethane at 20℃; for 1h; Inert atmosphere; Molecular sieve; | |
60% | Stage #1: 1,12-dodecandiol With phosphorus pentoxide In dichloromethane; dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: With triethylamine In dichloromethane; dimethyl sulfoxide at 20℃; for 0.5h; | |
60% | With phosphorus pentoxide; triethylamine In dichloromethane; dimethyl sulfoxide at 20℃; for 0.5h; | |
60% | Stage #1: 1,12-dodecandiol With phosphorus pentoxide In dichloromethane; dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: With triethylamine In dichloromethane; dimethyl sulfoxide at 20℃; for 0.5h; | Dodecanedial (6): Dialdehyde 6 was synthesized from 1 , I 2-dodecandiol (3.50 g, 1 7.3 mmoi) according to the general procedure for Alcohol oxidation (Albright--.Onodera conditions) (see section 2.1). 6 (2.06 g, 60%) was obtained as a white solid after purification by column chromatography on sihca gel using hexane/EtOAc (95:5 to 90:10) as the eluent. ‘H NMR data matched previously reported data. |
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane for 20h; | ||
With 2,2'-azinobis(3-ethylbenzthiazolinesulfonate); horse-radish peroxidase; choline oxidase from Arthrobacter cholorphenolicus, mutant S101A/D250G/F253R/V355T/F357R/M359R In aq. phosphate buffer at 30℃; for 24h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 1,12-dodecandiol With trichlorophosphate In toluene at 110℃; Inert atmosphere; Stage #2: With water at 5 - 90℃; | 3.3. General Procedure for the Conventional Heating Synthesis(Method 1). General procedure: The following procedure was adapted fromsynthesis reported for similar compounds [18]. Phosphorusoxychloride (30.66 g; 200mmol) and the diol (5.9; 8.01; 10.11 g(resp., for = 6, 9, or 12); 50mmol) were added underargon successively to a round bottomflask containing 120mLof toluene. The mixture was refluxed for 8 to 10 h undermagnetic stirring.The solution was then concentrated with arotary evaporator and the viscous residue was coevaporatedtwice with 100mL of toluene.In the second step the obtained residue was hydrolyzedby 100mL of cold water. Distilled water was added carefullyto the residue, previously cooled (5-10∘C). Then the solution was warmed down to 90∘C and stirred for 2 to 3hours. During the hydrolysis, a white precipitate appearedand was isolated after water filtration. The obtained whitesolid was dissolved in 100mL of ethanol which was thenevaporated. This operation was repeated twice in order toremove the remaining HCl. The residue was finally dissolvedin methanol/ethyl acetate (1/4) (v/v) and the solution was leftto precipitate overnight (in a freezer for compounds I andII, at r.t for compound III). The white powder was filtered,washed with diethyl ether, and dried in desiccators. |
With water; trichlorophosphate 1.) benzene, reflux, 3 h, 2.) reflux, 1 h; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridine at 0℃; for 2.5h; | |
84% | With triethylamine In dichloromethane at 0 - 20℃; for 6h; | Dodecane-1,12-diyl bis(4-methylbenzenesulfonate): Dodecane-1,12-diyl bis(4-methylbenzenesulfonate): A solution of Dodecane-1,12-diol (500 mg, 2.4 mmol) in anhydrous DCM (15 mL) charged with triethylamine (749 mg, 7.4 mmol) and stirred at 0°C for 10 min. The reaction was charged with p-toluene sulfonyl chloride (843.6 mg, 7.4 mmol) and stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between H2O (30 ml) and ethyl acetate (3 X 50 ml) and separated. The aqueous was re-extracted with ethyl acetate (2 X 20 ml) and combined organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo resulting in crude product. The crude was purified by column chromatography on silica gel (100-200 mesh), eluting with 5% methanol in chloroform to afford 872.2 mg (84% yield) of the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): = 7.82- 7.74 (m, 4H), 7.52- 7.44 (m, 4H), 4.00 (t, J = 6.3 Hz, 4H), 2.42 (s, 6H), 1.59- 1.47 (m, 4H), 1.26- 1.11 (m, 16H). |
83.3% | With pyridine In dichloromethane at 5 - 15℃; for 0.333333h; |
80% | With 4-methyl-morpholine In tetrahydrofuran at 20℃; | |
76% | Stage #1: p-toluenesulfonyl chloride With triethylamine In dichloromethane for 0.166667h; Inert atmosphere; Stage #2: 1,12-dodecandiol In dichloromethane at 0 - 20℃; Inert atmosphere; | |
63% | With pyridine at 0℃; | |
53% | Stage #1: 1,12-dodecandiol With triethylamine In dichloromethane for 0.5h; Stage #2: p-toluenesulfonyl chloride In dichloromethane at 20℃; for 18h; | |
32% | With potassium hydroxide In tetrahydrofuran at 20℃; for 18h; | |
With dmap In dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium at 120℃; for 2h; | |
47% | Stage #1: 1,12-dodecandiol With sodium hydride In 1,2-dimethoxyethane; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: dimethyl sulfate In 1,2-dimethoxyethane; mineral oil at 20℃; for 48h; Inert atmosphere; Stage #3: With ammonium chloride In 1,2-dimethoxyethane; water; mineral oil Inert atmosphere; Saturated solution; | 12-Methoxydodecan-1-ol Sodium hydride (60% dispersion in mineral oil, 2.17 g, 54.4 mmol, 1.1 eq) was added to a solution of 1,12-dodecanediol (10.0 g, 49.4 mmol, 1 eq) in DME (35 mL) cooled to 0 °C. The solution was allowed to warm to ambient temperature and stirred for 1 h. Dimethyl sulfate (4.65 mL, 49.4 mmol, 1 eq) was added and the reaction was stirred for 48 h. The reaction was quenched with a saturated solution of NH4Cl (35 mL). The quenched mixture was extracted with EtOAc (4×35 mL). The organic layer was washed with brine (35 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified using flash column chromatography (10 -40% EtOAc/petrol) to yield the mono protected alcohol as a white solid (5.06 g, 47%). νmax (liquid film)/cm-1 3371 (O-H), 2993 (C-H), 2921 (C-H), 2850 (C-H), 1739, 1461, 1122, 1035, 755. δH (400 MHz, CDCl3) 3.59 (2H, t, J=8.0, CH2OH), 3.34 (2H, t, J=8.0, CH2OMe), 3.31 (3H, s, CH2OCH3), 1.97 (1H, s, CH2OH), 1.51-1.56 (4H, m, 2×OCH2CH2), 1.22-1.34 (16H, m, 8×CH2); δC (100 MHz, CDCl3) 72.9, 62.6, 58.5, 32.7, 29.6, 29.5 (5C), 29.4, 26.1, 25.7. HRMS (FI) calculated for C13H28O2 [M+] 216.2089, found 216.2089. M.p = 31-33 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With pyridine at 0℃; | |
With triethylamine In dichloromethane at 0℃; for 5h; | 4.1.12. 1,12-Diiodododecane 14 To a solution of 1,12-dodecanediol (1.06 g, 5.23 mmol) and Et3N (2.9 mL, 20.9 mmol) in CH2Cl2 (17 mL) was added MsCl (1.01 mL,13.1 mmol) at 0 C. The reaction mixture was stirred for 5 h at0 C. After the reaction had been completed, the mixture was extracted with ether. The organic layer was washed successively with saturated aqueous NH4Cl, water, and brine, dried over MgSO4, and concentrated. The crude product was dissolved in acetone(20 mL) and NaI (3.90 g, 26 mmol) was added to this solution. After being stirred for 16 h, the reaction was quenched with water. The organic materials were extracted with ether and the organic layer was washed successively with water and brine, dried over MgSO4,and concentrated. The crude product was purified by silica gel column chromatography (hexane/AcOEt = 20:1) to give 14 (1.85 g,84%) as a colorless solid. The 1H NMR spectroscopic data of 14 were identical with those reported.15 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With triethylamine In tetrahydrofuran; toluene for 14h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: 1,12-dodecandiol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.333333h; Stage #2: benzyl bromide In tetrahydrofuran; mineral oil for 2h; Reflux; | |
65% | Stage #1: 1,12-dodecandiol With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1h; Stage #2: benzyl bromide With tetra-(n-butyl)ammonium iodide for 5h; Reflux; | |
50% | With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; for 6h; | 3 A solution of 1,12-dodecanediol (5.0 g, 24.7 mmoles) in a 2:1 THF/DMF mixture (36 ml) was added to a suspension of NaH (0.595 g, 24.83 mmoles) in DMF (18 ml) at 0°C. The mixture was stirred at 0°C for 2 hours. After that time, BnBr (4.42 g, 25.8 mmoles) was added at 0°C. The resulting mixture was stirred at room temperature for 4 hours. Then, the mixture was cooled at 0°C and H2O (75 ml) was added. The phases were separated, and the aqueous phase was extracted with Et2O (5 * 20 ml). The organic phase was washed with sat. NaCl (30 ml), dried with anhydrous MgSO4, filtered and the solvent was removed under reduced pressure. The product was purified by a chromatographic column (hexane/AcOEt, 10:1), obtaining (3.59 g, yield 50%) 12-benzyloxy-1-dodecanol (6), as a transparent oil. 1H-NMR (200MHz, CDCl3). δ 7.36-7.27 (5H, m, Ar-H), 4.51 (2H, s, -OCH2Ph), 3.60 (2H, t, J= 6.5 Hz), 3.45 (2H, t, J= 6.4 Hz), 1.60 (4H, m), 1.40 (16H, m). |
49% | With sodium hydride at 100℃; for 4h; | |
49% | With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran for 5h; Inert atmosphere; Reflux; | |
48% | With sodium hydride In tetrahydrofuran for 2h; Heating; | |
46% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 12h; | |
46.1% | Stage #1: 1,12-dodecandiol With sodium hydride In N,N-dimethyl-formamide for 0.0833333h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 40℃; Inert atmosphere; | |
45% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3h; | |
44% | Stage #1: 1,12-dodecandiol With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: benzyl bromide In tetrahydrofuran at 70℃; for 5h; | General procedure: To a stirred solution of 1,6-hexanediol (5a, 5.91 g, 50.0 mmol)in tetrahydrofuran (THF, 200 mL) at 0°C was added NaH(2.00 g, 50.0 mmol). After 20 min, BnBr (5.20 mL, 43.8 mmol) was added, and the reaction mixture heated under reflux for 5 h. After this time, a saturated aqueous NH4Cl solution was added, and the reaction mixture was extracted with ethylacetate. The combined organic layer was washed with brine,dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane-ethylacetate, 3 : 1-1 : 1) to afford 6a as a clear colorless oil (4.96 g,23.8 mmol, 54% yield based on BnBr). 6b (white wax, 8.94 g,30.5 mmol, 44%) was synthesized from 1,12-dodecanediol(5b, 14.2 g, 70.0 mmol) according to the above procedure. The spectroscopic data obtained for 6a and b corresponded with literature values. |
44% | Stage #1: 1,12-dodecandiol With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: benzyl bromide In tetrahydrofuran for 5h; Reflux; | General procedure: To a stirred solution of 1,6-hexanediol (5a, 5.91 g, 50.0 mmol) in tetrahydrofuran (THF, 200 mL) at 0°C was added NaH(2.00 g, 50.0 mmol). After 20 min, BnBr (5.20 mL, 43.8 mmol)was added, and the reaction mixture heated under reflux for5 h. After this time, a saturated aqueous NH4Cl solution wasadded, and the reaction mixture was extracted with ethylacetate. The combined organic layer was washed with brine,dried over anhydrous MgSO4, and filtered. The filtrate wasconcentrated in vacuo, and the resulting crude product waspurified by silica gel column chromatography (hexane-ethylacetate, 3 : 1-1 : 1) to afford 6a as a clear colorless oil (4.96 g,23.8 mmol, 54% yield based on BnBr). 6b (white wax, 8.94 g,30.5 mmol, 44%) was synthesized from 1,12-dodecanediol(5b, 14.2 g, 70.0 mmol) according to the above procedure. The spectroscopic data obtained for 6a and b corresponded with literature values.11,12) |
41.2% | Stage #1: 1,12-dodecandiol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; | C.1.70g 70g: 12-benzyloxydodecan-1-ol 14,05 g (68,76 mmol) 1, 12-dodecanediol were dissolved in 150 ml dry DMF. At 0 °C, 2,75 g (68,76 mmol) NaH (60 %) were added over a period of 30 min in four portions. The ice bath was removed and the solution was stirred for 3 h at room temperature, followed by the addition of a solution of 10,0 g (6,99 ml, 57,33 mmol) benzylbromide in 50 ml dry DMF at 0 °C. The reaction was stirred overnight at room temperature. After adding another 1,99 g (49,8 mmol) of NaH (60 %), stirring was continued for 4 h. The reaction mixture was poured into 500 ml ice-water and and extracted with diethylether and EtOAc. The organic layers were washed with sat. NaCl- solution, dried with MgS04 and evaporated. The crude product was purified on silica (0 to 60 % EtOAc in n-heptane) to yield 6,91 g (41,2 %) of the title compound 70g as white solid. LCMS-Method A: UV -wavelength [nm] = 220: Rt[min] = 2,09 Ionization method: ES+: [M+H]+ = 293,3 |
41.2% | Stage #1: 1,12-dodecandiol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; | C 72g: 12-Benzyloxydodecan-1-ol 14,05 g (68,76 mmol) 1,12-dodecanediol were dissolved in 150 ml dry DMF. At 0 °C, 2,75 g (68,76 mmol) NaH (60 %) were added over a period of 30 min in four portions. The ice bath was removed and the solution was stirred for 3 h at room temperature, followed by the addition of a solution of 10,0 g (6,99 ml, 57,33 mmol) benzylbromide in 50 ml dry DMF at 0 °C. The reaction was stirred overnight at room temperature. After adding another 1,99 g (49,8 mmol) of NaH (60 %), stirring was continued for 4 h. The reaction mixture was poured into 500 ml ice-water and and extracted with diethylether and EtOAc. The organic layers were washed with sat. NaCl-solution, dried with MgSO4 and evaporated. The crude product was purified on silica (0 to 60 % EtOAc in n-heptane) to yield 6,91 g (41,2 %) of the title compound 72g as white solid. LCMS-Method A: UV-wavelength [nm] = 220: Rt[min] = 2,09 Ionization method: ES+: [M+H]+ = 293,3 |
40.4% | Stage #1: 1,12-dodecandiol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 15h; Stage #2: benzyl bromide In N,N-dimethyl-formamide | |
40% | With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 16h; | |
40% | With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 16h; | I 2-(henzvloxy)dodecan- I -ol (12): Compound 12 was synthesized following a reported protocol (WO 2009/1 35977). |
38% | Stage #1: 1,12-dodecandiol With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 22h; | |
32% | With silver(l) oxide In dichloromethane for 168h; | |
With sodium hydride 1.) THF, 40 deg C, 80 min, 2.) THF, 60 deg C, 19 h; Yield given. Multistep reaction; | ||
With sodium hydride 1.) THF, 60 deg C, 1 h; 2.) 60-70 deg C, 5 h; Yield given. Multistep reaction; | ||
With sodium hydride In N,N-dimethyl-formamide | ||
With sodium hydride In N,N-dimethyl-formamide | ||
Stage #1: 1,12-dodecandiol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; | ||
With sodium hydride In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With dmap; triethylamine In dichloromethane at 0 - 20℃; | 2-Hydroxyethyl Dodecanoate (13a) General procedure: Ethanediol (1.1 mL, 20.00 mmol), Et3N (5.10 g, 50.0 mmol) and DMAP (122 mg, 1.0 mmol) were dissolved in 200 mL anhydrous CH2Cl2. The C11H23COCl (2.18 g, 10.00 mmol) was added dropwise at 0 °C. The mixture was warmed up to room temperature and kept stirring overnight then washed with 1 N HCl solution, water, saturated aqueous solution of NaHCO3and brine, successively. The organic phase was dried overNa2SO4, filtered, and then concentrated. The crude mixture was purified by column chromatography (petroleum ether-EtOAc 30 : 1) on silica gel to afford 13a as a colorless oil (1.51 g, 62%). |
27% | With dmap; triethylamine In dichloromethane at 20℃; for 18h; Inert atmosphere; | |
99.9 % Chromat. | With silica gel In cyclohexane at 80.2℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 1H-imidazole; dmap In dichloromethane; N,N-dimethyl-formamide at 25℃; | 1.1 12-tert-butyldimethylsiloxy dodecanol (3) 10.0 g of 1, 12-dodecanediol (1) and 6.7 g of imidazole were placed in 50 mL of DMF and 160 mL of CH2Cl2,A solution of 8.4 g of t-butyldimethoxysilane (TBDMSCl, 2) in 50 mL of CH2Cl2 was added dropwise at about 25 ° C, and 0.3 g of 4-dimethylaminopyridine (DMAP) was added dropwise to maintain the temperature. TLC monitoring (PE: EA = 15: 1) When double-protected by-products were observed, the ice bath was cooled and 100 mL of water was added to the quenching reaction. The organic phase was separated and dried over anhydrous magnesium sulfate. Filter,Steamed to give a colorless oil.Column chromatography (petroleum ether: ethyl acetate = 100: 1, gradient elution, mobile phase adjusted to petroleum ether:Ethyl acetate = 10: 1) The polarized imidazole and DMAP were removed and the product was collected and evaporated to concentrate to remove the solvent to give 15.4 g of product as a colorless oil(Theoretical yield 15.7 g, yield 98%). |
78% | With 1H-imidazole In N,N-dimethyl-formamide | |
61% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 17h; |
57% | Stage #1: 1,12-dodecandiol With sodium hydride In tetrahydrofuran; mineral oil at 55℃; Inert atmosphere; Stage #2: tert-butyldimethylsilyl chloride In tetrahydrofuran at 20℃; for 2h; | |
55% | With sodium hydride In tetrahydrofuran | |
53% | With 1H-imidazole In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; | 1. Synthetic Scheme and Characterizations of Compounds TBSCl(4.47g, 29.70 mmol) was added slowly to the solution of dodecane diol (6.0 g, 29.70 mmol) and imidazole (2.02 g, 29.70mmol) in DMF/THF= 3/1(40 mL) at 0 C. After stirring for 30 min at room temperature, the reactionmixture was diluted with excess water and extracted with EtOAc. The organicphase was washed with water, and brine, dried over dried over MgSO4,filtered, and concentrated under reduced pressure. The crude residue waspurified by silica gel column chromatography (20% EtOAc in hexane) to afford 6 (5.0 g, 15.80 mmol, 53%) as a sticky mass. |
51.2% | With 1H-imidazole In dichloromethane at 20℃; Cooling with ice; | |
48% | With 1H-imidazole In N,N-dimethyl-formamide | |
45% | With 1H-imidazole; dmap In dichloromethane at 85℃; for 1h; Inert atmosphere; Microwave irradiation; | |
40% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 17h; | |
39% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 18h; | |
31% | With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere; | |
18% | With 1H-imidazole In dichloromethane at 20℃; | |
In dichloromethane for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tetra-(n-butyl)ammonium iodide; sodium hydride In N,N-dimethyl-formamide; toluene; mineral oil at 0 - 20℃; for 15h; | 1,12-Dipropargyloxydecane (2) To a cooled (0°C) solution of compound 1 (commercially available) (5g, 24.7 mmol) in anhydrous DMF (60 mL) was added sodium hydride in small portions (55% in mineral oil, 6.5 g, 148.2 mmol) under stirring. Propargyl bromide (80% w/w in toluene, 11 g, 74.1 mmol) was added followed by TBAI (0.91 g, 2.4 mmol), and stirring was continued for 15 hours at room temperature. The reaction was quenched with methanol (10 mL) and stirred a further 30 min. After addition of DCM (200 mL) the solution was washed with water (3x50 ml_) then brine (50 ml_), the organic layer dried (Na2SO4) and concentrated under reduced pressure. Product 2 was isolated after purification on silica gel (hexane/ethyl acetate 100/0 then 97/3) as a colorless liquid. Yield: 4.48 g (65%). 1H NMR (300 MHz, in CDCI3) δ 1.22-1.43 (m, 16H, CH2), 1.52-1.66 (0188) (m, 4H, CH2CH20), 2.43 (t, J= 2.4 Hz, 2H, CH propargyl), 3.52 (t, J= 6.6 Hz, 4H, CH2CH2O), 4.15 (d, J= 2.4 Hz, 4H, CH2 propargyl). (0189) 13C NMR (75 MHz, in CDCI3) δ 26.08, 29.42, 29.50, 29.55 (CH2, CH2CH2O), 57.97 (CH2 propargyl), 70.31 (CH20), 74.01 (CH propargyl). |
65% | Stage #1: 1,12-dodecandiol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; Inert atmosphere; Stage #2: propargyl bromide With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide; toluene; mineral oil at 20℃; for 15h; Inert atmosphere; | |
With sodium hydride 1.) THF, 45 deg C, 48 h, 2.) 55 deg C, 40 h; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 4-pyrrolidin-1-ylpyridine; dicyclohexyl-carbodiimide In pyridine | |
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 72h; | ||
Stage #1: 1,12-dodecandiol; Thioctic acid With dmap In dichloromethane at 20℃; for 0.166667h; Molecular sieve 60 A; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12.17h; Darkness; | 26 α-Lipoic acid (2.48 g, 12 mmol, 1.2 equiv.) and the compounds containing two hydroxyl groups (1 ,12-dodecanediol ("1 ,12-DD")) (10 mmol OH, 1.0 equiv.) in 20 mL of anhydrous dichloromethane (DCM) were reacted with 4-(dimethylamino)-pyridine (DMAP, 1.47 g, 12 mmol, 1.2 equiv.) in the presence of molecular sieve (60 A, 10-20 mesh beads) for 10 min at room temperature. /V-(3-Dimethylaminopropyl)-/V- ethylcarbodiimide hydrochloride (EDCI, 2.3 g, 12 mmol, 1.2 equiv.) was added portionwise over 10 min and the reaction mixture was stirred for 12 h at room temperature in the dark, filtered, and then concentrated under vacuum to reduce the volume. The resulting reaction mixture was purified using silica gel by direct loading onto the column without further preparation. The solvent was removed under reduced pressure to give the products. See also International Application No. PCT/US08/88541 , which is incorporated herein by reference in its entirety as though fully set forth. |
Stage #1: 1,12-dodecandiol; Thioctic acid With dmap In dichloromethane at 20℃; for 0.166667h; Molecular sieve; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; without light; Molecular sieve; | 4 Example 4; Synthesis of α-lipoic acid derivative ALA2(1, 12-dodecanedioi) α-poic acid (2.48 g, 12 mmol, 1 2 equiv.) and 1 ,12-dodecanediol (10 mmo1 OH, 1.0 equiv.) in 20 ml_ of anhydrous dichloromethane (DCM) were reacted with A- (dιmethylamino)-pyridine (DMAP, 1.47 g, 12 mmol, 1.2 equiv,) in the presence of molecular sieve (60 A, 10-20 mesh beads) for 10 min at room temperature, N-(3- DimethyIamιnopropyl)-N-ethylcarbodiimide hydrochloride (EDCI, 2.3 g, 12 mmol, 1.2 equiv,) was added portionwise over 10 min and the reaction mixture was stirred for 12 h at room temperature in the dark, filtered, and then concentrated under vacuum to reduce the volume. The resulting reaction mixture was purified using silica gel by direct loading onto the column without further preparation. The solvent was removed under reduced pressure to give the products. 1H NMR and 13C NMR spectra of the compound are provided U.S. Provisional Application Serial No. 61/018,749, filed January 3, 2008, andInternational Application Publication No WO 2009/086547, filed December 30, 2008, herein incorporated by reference in their entirety as though fully set forth, provide additional examples of synthesizing α-hpoic acid derivatives that are used in the present invention. Scheme 4 Synthesis of α-Iipoic acid derivatives B | |
Stage #1: 1,12-dodecandiol; Thioctic acid With dmap In dichloromethane at 20℃; for 0.166667h; Molecular sieve; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12.1667h; Darkness; | 2 Example 2 Synthesis of a-lipoic acid derivative ALA2(1 ,12-dodecanediol) a-Lipoic acid (2.48 g, 12 mmol, 1.2 equiv.) and 1,12-dodecanediol (10 mmol OH, 1.0 equiv.) in 20 mL of anhydrous dichloromethane (DCM) were reacted with 4- (dimethylamino)-pyridine (DMAP, 1.47 g, 12 mmol, 1.2 equiv.) in the presence of molecular sieve (60 A, 10-20 mesh beads) for 10 min at room temperature. N-(3- Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDCI, 2.3 g, 12 mmol, 1.2 equiv.) was added portionwise over 10 min and the reaction mixture was stirred for 12 h at room temperature in the dark, filtered, and then concentrated under vacuum to reduce the volume. The resulting reaction mixture was purified using silica gel by direct loading onto the column without further preparation. The solvent was removed under reduced pressure to give the products. 1H NMR and 13C NMR spectra of the compound are provided. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: C12H13O2(CH3)3(O)(OO) With sodium tetrahydroborate; amberlyst-15 In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 1,12-dodecandiol In dichloromethane at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dmap; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With HY-Zeolite In chloroform for 4.5h; Heating; | |
79% | With sulfuric acid In toluene at 100℃; for 8h; | 1.1.2.1 1.2.1Synthesis of 12-hydroxydodecyl acetate (5) will1,12-dodecanediol(405 g, 2 mol), acetic acid (120 g, 2 mol)Dissolved in 2L of toluene, adding 3%mol of 98% concentrated sulfuric acid,Stir the reaction at 100 ° C for 8 h,Neutralize with a saturated sodium carbonate solution to neutral, separate the organic layer,The aqueous layer was extracted with toluene (300 mL×3), and the organic layers were combined and washed with water.Drying over anhydrous sodium sulfate and concentrating to give a crude product.(The eluent is petroleum ether and ethyl acetate,The volume ratio of petroleum ether to ethyl acetate is 18-22:1) purification386g of white solid 5 is obtained,The yield was 79%. |
33% | With sulfuric acid In water; toluene Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With iodine In acetonitrile at 120℃; for 0.0666667h; Microwave irradiation; chemoselective reaction; | 4. 2. Typical Procedure for Iodinationof Alcohol General procedure: To a suspension of polymer-bound triphenylphosphine (1.2 mmol) in anhydrous acetonitrile (10 mL) were added iodine (1 mmol) and 1,6-hexanediol diol (1mmol). The reaction mixture was irradiated in microwave reactor at 120 °C for 3 min. The reaction mixture was filtered over a filter paper and washed with chloroform.The filtrate was extracted with aqueous sodium thiosulfate solution and dried with anhydrous sodium sulfate.The reafter, solvent was removed under reduced pressure to obtain 6-iodohexan-1-ol (30) in 93% |
With hydrogen iodide In toluene at 90℃; for 6h; | ||
Multi-step reaction with 2 steps 1: 47percent HBr / toluene / Heating 2: NaI / acetone / Ambient temperature |
Multi-step reaction with 2 steps 1: aq. HBr 2: NaI | ||
Multi-step reaction with 2 steps 1: (i) CCl4, (ii) KPF6 2: KI / dimethylformamide | ||
With hydrogen iodide In water; toluene at 90℃; for 6h; | ||
Multi-step reaction with 2 steps 1: hydrogen bromide / toluene / Reflux; Inert atmosphere 2: sodium iodide / acetone / Inert atmosphere; Molecular sieve; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: 1,12-dodecandiol With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Stage #2: chloromethyl methyl ether In tetrahydrofuran at 20℃; for 16h; | 3.3.1. General Procedure for the Monoprotection of 3a and 3b General procedure: To a stirred solution of 3a or 3b (4.30 mmol) in THF (12 mL) was added NaH (60%, 181 mg,4.52 mmol) at 0 C, and the reaction mixture was stirred at 0 C for 15 min. To the reaction mixture wasadded MOMCl (0.35 mL, 4.52 mmol), and the resulting mixture was stirred for 16 h at room temperature.The reaction was quenched with saturated NH4Cl aqueous solution, and the aqueous mixture wasextracted with CH2Cl2 (3 3 mL). The organic extracts were combined, dried, and evaporated to givea colorless oil, which was chromatographed on a SiO2 column (15 g, EtOAc/n-hexane = 1/10-1/5) togive 4a [26] or 4b. |
40% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With 1H-imidazole In dichloromethane; N,N-dimethyl-formamide at 20℃; | |
68% | With 1H-imidazole; dmap In dichloromethane at 25℃; for 8h; Inert atmosphere; | |
59% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 15h; |
59% | Stage #1: 1,12-dodecandiol With 1H-imidazole In dichloromethane at 20℃; for 0.583333h; Stage #2: tert-butylchlorodiphenylsilane In dichloromethane at 20℃; for 0.166667h; | |
50% | With 1H-imidazole In N,N-dimethyl-formamide | |
46% | With 1H-imidazole In dichloromethane; N,N-dimethyl-formamide at 20℃; | c c, synthesis of compound 8 1,12-dodecanediol (10 g, 49.42 mmol) was weighed and dissolved in a mixed solution of 100 ml of DCM and 40 mL of DMF, and then imidazole (10.09 g, 148.26 mmol) and TBDPSCl (15.62 g, 56.83 mmol) were added in sequence, and the reaction was carried out at room temperature. The plate was monitored until the disappearance of the starting material, 100 mL of water was added, and the mixture was extracted three times with 100 ml of LDCM. The organic phase was combined, concentrated in vacuo, and then purified by column to yield 10.01 g of pure product, yield 46%. |
42% | With 1H-imidazole In dichloromethane at 20℃; | |
38% | With 1H-imidazole In dichloromethane; N,N-dimethyl-formamide at 20℃; for 19h; | |
With 1H-imidazole In tetrahydrofuran for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With tricarbonyl(η(4)-cycloocta-1,5-diene)iron; phenylsilane In tetrahydrofuran at 20℃; for 24h; UV-irradiation; Inert atmosphere; chemoselective reaction; | |
91% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; | |
Multi-step reaction with 2 steps 1: sulfuric acid / Heating 2: LiAlH4 / diethyl ether / 0 °C |
Stage #1: 1,12-dodecanedioic acid With 4-methyl-morpholine; chloroformic acid ethyl ester In tetrahydrofuran at 2℃; for 0.25h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 2℃; | 3.1. Samples General procedure: Samples of 1,10-decanediol, DEDOL (98% pure) and 1,12-dodecanediol, DODOL (99% pure) fromSigma-Aldrich were used as received. Then, 1,11-undecanediol (UNDOL) and 1,13-tridecanediol(TRDOL) were synthesized from the corresponding dicarboxylic acids by a reduction procedurereported elsewhere [41]. First, N-methylmorpholine (1.01 mL, 9.24 mmol) and ethyl chloroformate(0.88 mL, 9.24 mmol) [42] were mixed with a dissolution (2 °C) prepared with 1 g of undecanedioicacid (4.62 mmol) in 50 mL of THF. This mixture was stirred for 15 min and a precipitate ofN-methylmorpholine hydrochloride was obtained. This precipitate is filtered, washed with THFand mixed at 2 °C with 7 mL of an aqueous sodium borohydride solution (0.56 g, 14.78 mmol). Then,120 mL of water was added after degassing the solution. Finally, ethyl acetate was used to obtainthe organic extract that, subsequently, was dried over sodium sulfate. Purified UNDOL is obtainedfor concentrating them under reduced pressure and recrystallized in ethyl ether. All this synthesiswas also used to obtain TRDOL but, in this case, 1,13-tridecanedioic acid was selected as the startingproduct. TRDOL was recrystallized in toluene instead of ethyl ether in order to evaluate possiblechanges on crystallite morphology of isostructural compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium aluminium tetrahydride In tetrahydrofuran at -50 - 20℃; for 27h; Heating / reflux; | 1 Next, 0.5 g (13 mmol) of lithium aluminium hydride was added to the tetrahydrofuran, and the mixture kept at -50° C. After gradually dripping the aforesaid acid chloride solution into this solution, the mixture was returned to room temperature, and heated under reflux for 3 hours. Subsequently, it was stirred at room temperature for 24 hours, and ethyl acetate followed by a saturated aqueous solution of sodium sulphate was added until the bubbles disappeared. Next, the reaction solution was placed under reduced pressure to distil off the solvent, the solid obtained was suspended in chloroform and filtered, and the filtrate was distilled under reduced pressure. The solid obtained was recrystallized from a solution of hexane/ethyl acetate=2/1, and 1.5 g of 1,12-dodecane diol was obtained as a white solid (yield=74%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1,12-dodecandiol; 5'-O-(4,4'-dimethoxytrityl)-2'-deoxythymidine-3'-O-[O-(2-cyanoethyl)-N,N'-diisopropylphosphoramidite] With 1H-tetrazole In tetrahydrofuran at 20℃; for 24h; Stage #2: With tert.-butylhydroperoxide In tetrahydrofuran; water for 1h; Stage #3: With ammonia In tetrahydrofuran; water for 24h; | 1 0.14 g (0.7 mmol) of this 1,12 dodecane diol and 0.2 g (3 mmol) of 1H-tetrazole were dissolved in tetrahydrofuran, and 1.0 g (1.4 mmol) of 5'-O-dimethoxytrityl-2'-deoxythymidine-3'-O-[O-(2-cyanoethyl)-N,N-diisopropylphosphoramidite] was added. After stirring at room temperature for 24 hours, 0.4 ml of a 70% aqueous solution of t-hydroperoxide was added to the reaction solution, and stirred for one hour. Next, 8 ml of a 28% aqueous solution of ammonia was added and stirred for 24 hours, the solvent was distilled off under reduced pressure, and the solid obtained was purified by silica gel column chromatography (eluent: chloroform/methanol=4/1). The solid obtained was dissolved in chloroform, 0.5 ml of trifluoroacetic acid was added, and the solid which separated was rinsed with chloroform. This was re-precipitated from chloroform/methanol=1/1 solution to give 0.2 g of 1,12-(dodecanedioxy)bis(3'-phosphatidyl-2'-deoxythymidine) (Compound 1) as a white powder (yield 35%). The 1H-NMR spectrum of this compound is shown in . In the 1H-NMR (heavy water, 25° C.), signals due to the methylene groups of long chain alkyl groups having a ς value of 1.2-1.3 ppm, 1.6 ppm, 3.8 ppm, and signals due to the methyl protons bonded at the 5 position of the pyrimidine base in the vicinity of 1.9 ppm, the protons bonded at the 2' position of deoxyribose in the vicinity of 2.4 and 2.6 ppm, the methylene protons bonded to the 5' position of deoxyribose in the vicinity of 3.8 ppm, the proton bonded to the 4' position of deoxyribose in the vicinity of 4.2 ppm, the proton bonded to the 3' position of deoxyribose in the vicinity of 4.8 ppm, the proton bonded to the 1' position of deoxyribose in the vicinity of 6.3 ppm, the proton bonded to the 6 position of the pyrimidine base in the vicinity of 7.7 ppm, and the imido group NH proton bonded to the 3 position of the pyrimidine base in the vicinity of 9.2 ppm, were respectively observed. [0039] The physical properties and detailed mass spectral analysis results for this compound are as follows. [0040] Rf value of thin layer chromatography=0.71(chloroform/methanol=1/1) [0041] Melting point=232° C. (decomposition) [0042] Detailed mass spectrum analysis value (as [M-H+]-), [0043] calculated value: 809.2775, [0044] experimental value: 809.2770. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In tetrahydrofuran; water | 15 Dodecanedinitrile reductive hydrolysis in THF/water using RuHCl(H2)(PCy3)2 EXAMPLE 15 Dodecanedinitrile reductive hydrolysis in THF/water using RuHCl(H2)(PCy3)2 A mixture of 0.066 mmol RuHCl(H2)(PCy3)2, 2.95 mmol dodecanedinitrile, 15 mL water and 20 mL THF was stirred in a Fisher-Porter tube at 80° C. under 860 kPa H2. After 22.1 hours, gc analysis showed that the dinitrile conversion was 97% and the yield of 1,12-dodecanediol was 78%. Most of the remaining dinitrile (17%) was accounted for as 12-hydroxydodecanenitrile, the half-reductively-hydrolyzed intermediate, suggesting that the ultimate yield of diol would have been higher at longer reaction time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In toluene for 8h; Heating / reflux; | 3 A mixture of [Ethyl Undecanoate]-Isobutyl-POSS (from Hybrid Plastics, 4.0 mmol, 4.12 grams), 1,12-dodecanediol (2.0 mmol, 0.40 grams), and para-toluenesulfonic acid as catalyst (0.10 mmol, 0.02 grams) in 30 mL of toluene was heated to reflux for about 8 hours. The mixture was then cooled to room temperature, diluted with 30 mL ethyl acetate and washed with deionized water to remove acid catalyst, then with brine solution. The ethyl acetate extract was dried over anhydrous magnesium sulfate, filtered and concentrated to afford a transparent solid in quantitative yield. 1H-NMR spectroscopy confirmed formation of the product. The reaction scheme is shown below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 40℃; for 12h; | |
56% | Stage #1: 1,12-dodecandiol; Methacryloyl chloride With pyridine In tetrahydrofuran for 19.5h; Stage #2: In cyclohexane Reflux; | |
With pyridine at 20℃; |
With N-ethyl-N,N-diisopropylamine | ||
With N-ethyl-N,N-diisopropylamine | ||
With N-ethyl-N,N-diisopropylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 26% 2: 34% | With tributylphosphine; diamide In tetrahydrofuran at 60℃; Darkness; Inert atmosphere; | Synthesis of 2n General procedure: 3,4-dihydroxy-2,5-thiophenedicarboxylic acid diethyl ester 1 (1.3 g, 5 mmol), cis-2-Butene-1,4-diol (410 ul, 5mmol), and tributylphosphine (TBP) (3.1 ml, 12.6 mmol) were added successively to 10 mL THF in two-necked flask. Under exclusion of light, the system was then purged with argon. N,N,N’,N’-Tetramethylazodicarboxamide (TMAD) (2.15 g, 12.5 mmol) was dissolved in 60 mL THF and added to the above solution in 30 minutes with a syringe. After the addition, the mixture was warmed to 60 oC for 36 h. The solvent was then removed under reduced pressure. The crude product was purified by column chromatography (SiO2, CH2Cl2) to give 2a as white solid in 78% yield (1.22 g). Mp: 80 oC. 1H-NMR (CDCl3, 250 MHz) δ 1.25 (t, J = 7.1 Hz, 6H), 4.20 (m, J = 7.1 Hz, 4H), 4.95 (d, J = 3.3 Hz, 4H), 5.87 (m, J = 3.3 Hz, 2H). 13C-NMR (CDCl3, 62.5 MHz) δ 13.98, 60.91, 69.35, 117.48, 129.67, 150.45, 160.17. HRMS (EI) calcd for C14H16O6S [M]+ 312.0668, found 312.0670. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 1,12-dodecandiol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | |
82% | Stage #1: 1,12-dodecandiol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; for 24h; | |
49% | Stage #1: 1,12-dodecandiol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran at 0 - 20℃; for 24.5h; Inert atmosphere; |
46% | With sodium hydride In N,N-dimethyl-formamide; toluene; mineral oil for 12h; | 12-Propargyloxydodecan-1 -oi (7) To a cooled (0°C) solution of compound 1 (commercially available) (4g, 20 mmol) in anhydrous DMF (100 mL) was added sodium hydride in small portions (55% in mineral oil, 2.5 g, 109 mmol) under stirring. Propargyl bromide (80% w/w in toluene, 9 g, 60 mmol) was added dropwise, and stirring was continued for 12 hours at low temperature. The reaction mixture was concentrated under reduced pressure. The resulting mixture was poured into water and extracted with DCM. The extracts were combined, washed with water (3x50 mL) then brine (50 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure. Product 7 was isolated after purification on silica gel (hexane/ethyl acetate 6/4) as a brown solid. Yield: 2.24 g (46%). 1H NMR (300 MHz, in CDCI3) δ 1.19-1.30 (m, 16H, CH2), 1.46-1.59 (m, 4H, CH2CH2O), 2.37 (large s, 1 H, OH), 2.40 (t, J= 2.4 Hz, 1 H, CH propargyl), 3.46 (t, J= 6.6 Hz, 2H, CH2O), 3.56 (t, J= 6.7 Hz, 2H, CH2O), 4.08 (d, J= 2.4 Hz, CH2 propargyl). (0194) 13C NMR (75 MHz, in CDCI3) δ 25.74, 26.03 (CH2), 29.39, 29.43, 29.53, 29.58 (CH2 + CH2CH2O), 32.70 (CH2CH2O), 57.92 (CH2 propargyl), 62.72, 70.22 (CH2O), 74.13 (CH propargyl). |
46% | Stage #1: 1,12-dodecandiol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; Inert atmosphere; Stage #2: propargyl bromide With N,N,N-tributyl-1-butanaminium iodide In N,N-dimethyl-formamide; toluene; mineral oil at 10℃; for 12h; Inert atmosphere; | |
26% | Stage #1: 1,12-dodecandiol With potassium-t-butoxide In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With Pt-Sn/γ-Al2O3 In o-xylene at 145℃; for 24h; Inert atmosphere; | A general procedure for the direct synthesis of diamines 3 from the N-alkylation of amines 2 with diols 1: General procedure: Under nitrogen atmosphere, to a 15-mL Pyrex glass screw-cap tube were added diol 1 (1.0 mmol), amine 2 (2.0 mmol), Pt-Sn/γ-Al2O3 catalyst (200 mg, 0.5 mol % Pt), and o-xylene (5 mL). The resultant mixture was stirred in the sealed tube at 145 °C for 24 h. After cooled to ambient temperature, the catalyst was removed by centrifugation and washed with CH2Cl2 (3 × 5 mL). The combined supernatant was condensed under reduced pressure and subjected to purification by silica gel column chromatography (eluent: petroleum ether (60-90 °C)/EtOAc = 20:1, v/v), affording diamine 3. The known compounds were identified by comparison of their NMR features with the reported data or of their GC traces with those of the authentic samples. The spectroscopic features of these known compounds are in good agreement with those reported in the literatures. All the new products were characterized by NMR and HRMS techniques. |
98 %Spectr. | With tris(2,4-pentanedionato)ruthenium(III); methanesulfonic acid; hydrogen; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In 1,4-dioxane at 220℃; for 20h; Autoclave; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With sodium hydride In toluene at 80℃; for 96h; | 4-1 Example 4 4-1: Synthesis of 1,12-bis-(12-bromododecyloxy)-dodecane Br-C12H24-Br + HO-C12H24-OH → Br-C12H24-O-C12H24-O-C12H24-Br Sodium hydride (60%, 652 mg, 16.3 mmol) washed with hexane was suspended in toluene (3 ml), 1,12-dodecanediol (1.50 g, 7.41 mmol) was added, 1,12-dibromododecane (6.08 g, 18.5 mmol) was added and the mixture was stirred at 80°C for 4 days. The reaction mixture was cooled to room temperature, and pure water (30 ml) was added dropwise thereto in a water bath to quench the reaction. The mixture was extracted with chloroform (100 ml), and washed 3 times with 1N hydrochloric acid (30 ml), 3 times with 5% aqueous sodium hydrogen carbonate solution (30 ml), and once with 20% aqueous sodium chloride solution (30 ml). The organic layer was dried over sodium sulfate and the solvent of the filtrate was evaporated. The residue was isolated and purified by silica gel column chromatography, and precipitated with methanol (50 ml) to give 1,12-bis-(12-bromododecyloxy)-dodecane (yield 56%). 1H-NMR (300MHz) 1.20-1.65 (56H, br, alkyl-H) 1.85 (4H, dt, -CH2-CH2-Br) 3.39 (12H, m, -O-CH2, -CH2-Br) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56 %Chromat. | With methanol; glycolic Acid at 300℃; for 4h; Inert atmosphere; Supercritical state; Stainless steel pipe reactor; | 30 Example 30 Into a pipe reactor having a volume of 10 mL, dodecamethyleneimine (0.10 g), methanol (3.00 g), and glycolic acid (0.12 g) were added, and the reactor was tightly closed after nitrogen substitution at room temperature. The reactor was put into an electric furnace heated to 300°C, and reaction was carried out for 240 minutes (pressure of 14.5 MPa). Thereafter, the reactor was taken out from the electric furnace and quickly cooled by cold-water bath to stop the reaction. After confirming that the reactor had been sufficiently cooled, the reaction mixture was taken out with methanol and collected. The obtained reaction mixture and anisole as an internal standard substance were weighed as an analysis sample for gas chromatography analysis. An integrated value was calculated by gas chromatography analysis, and the yield was determined from a prepared calibration line table. As a result thereof, the yield of 1,12-dodecanediol was 56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With Amberlyst-15 In dichloromethane for 2.5h; Reflux; regioselective reaction; | General procedure for selective mono PMB protection of diols: (Z)-4-((4-Methoxybenzyl)oxy)but-2-en-1-ol (Table 5, entry 1): A mixture of cis-2-butene-1,4-diol (200 mg, 2.3 mmol), p-anisyl alcohol (345 mg, 2.5 mmol), and catalytic amount (10% w/w, 20 mg) of Amberlyst-15 resin in anhydrous CH2Cl2 (10 mL) was refluxed. After 3 h, the crude reaction mixture was filtered through a Whatman filter paper and the residue washed with CH2Cl2, dried (over anhydrous Na2SO4), filtered and concentrated in vacuo and purified using flash chromatography (pet ether/ethyl acetate 70:30) to provide 401 mg (85%) of pure product as a colorless dense liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; for 10h; | 2 In a typical preparation, 1.00 g (5.15 mmol) of 2,3,4,5-tetrafluorobenzoic acid in anhydrous THF (20 mL) was stirred and cooled to -78° C. 4.53 mL of BuLi (2.5 M in hexanes, 2.2 eq) was added drop wise. The resulting suspension was further stirred for 3 hours at -78° C. MEL (0.38 mL, 1.2 eq) in anhydrous THF (2 mL) was added drop wise, and the mixture was stirred for another 0.5 hour. The mixture was then warmed to room temperature, and stirred for a further 20 minutes whereupon a white suspension was obtained. The reaction was quenched by drop wise addition of deionised water, acidified and extracted by ethyl acetate (3×30 mL). The extract was dried with anhydrous MgSO4, and evaporated to dryness at reduced pressure to give (2) as a white solid (yield=56%). 0.9 g of (2) was mixed with SOCl2 (5 mL) and 1 drop of DMF, and heated at 75° C. for 12 h. Excess SOCl2 was removed at reduced pressure to give (3) as a yellowish oil and used without further purification. To a solution of 1,12-dodecanediol (0.145 g, 0.61 mmol) and triethylamine (0.16 mL, 1.2 mmol) in anhydrous dichloromethane (5 mL) was added (3) (0.33 g, 1.4 mmol, 15 mol % excess) dissolved in anhydrous dichloromethane (5 mL). The mixture was stirred at room temperature for 10 hours, then washed by brine (3×10 mL), dried over anhydrous MgSO4 and evaporated to dryness at reduced pressure to give (4) as a colourless oil. This was purified by column chromatography (silica gel; eluting solvent, 2:1 hexane:dichloromethane) (yield=72%). (4) (0.30 g, 0.51 mmol) and NaN3 (0.33 g, 5.1 mmol) were dissolved in a DMF:water mixture (7 mL:5 mL) and heated to 95° C. for 30 hours. Water (10 mL) was added and the mixture extracted by ethyl acetate (20 mL×3), dried over MgSO4 and evaporated to dryness at a reduced pressure to give a yellow crude that was purified by column chromatography (silica gel; eluting solvent 2:1 hexane:dichloromethane) to give (5) as a white solid (yield=65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1,12-dodecandiol; Diethyl carbonate With titanium(IV) isopropylate at 200℃; for 4h; Inert atmosphere; Stage #2: With titanium(IV) isopropylate In 1,2-dichloro-benzene at 180℃; for 72h; Inert atmosphere; | 5 4.3. Synthesis of polycarbonate 4 General procedure: 1,6-Hexanediol (5.00 g, 42 mmol), diethyl carbonate (5.90 g, 50 mmol) and titanium tetra(isopropoxide) (12.0 mg, 4.23 × 10-2 mmol, 0.1 mol% with respect to the diol) were mixed together in a round-bottomed flask equipped with a fractionating column. The mixture was vigorously stirred and heated (ca. 200 °C) for 2 h under normal atmospheric pressure. Ethanol distilled off and the viscosity of the clear reaction mixture increased. After 2 h, the fractionating column was removed and the viscous product heated for another 2 h under vacuum (0.1 mm Hg). The reaction mixture was then cooled to ambient temperature, dissolved in a minimum amount of chloroform (40 mL) and precipitated into methanol (800 mL). The clear white precipitate was filtered off and dried at 40 °C and 0.1 mm Hg to yield polymer 4 (5.30 g, 87%) as a white powder. 4.2. CDP of polymer 1. A mixture of finely milled commercial polymer 1 (3.50 g, 13.8 mmol) and TBATPB (154.0 mg, 0.28 mmol, 3 mol%) in 1,2-dichlorobenzene (350 mL) was stirred and heated under reflux (ca 180 °C) in a nitrogen atmosphere for 5 d. The mixture was then cooled to 40 °C. The unreacted polymer that precipitated out was filtered off and the filtrate was evaporated to dryness. This gave the crude MCOs 11 (2.91 g, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With amine In tetrahydrofuran at 0℃; for 24h; | 2.2 Synthesis of ligands (Scheme 1) General procedure: To a solution of the respective alcohol (50 mmol) in CH2Cl2 (a-d and g-j) or THF (e-f), an excess of mesyl chloride (1.1 equivalents) in THF was slowly added at 0 °C in the presence of pyridine or triethylamine (1.1 equivalents). The reaction mixture was stirred for 24 h, after which time the complete consumption of the starting material (alcohol) was evidenced by TLC (eluent: dichloromethane). The solvent was then evaporated under reduced pressure and the residue thus obtained was washed twice with water and then with saturated brine solution. The product was purified by column chromatography and/or recrystallization. The alkyl mesylate thus obtained was then slowly added at 70 °C to an ethanol solution containing an excess of 1,2-ethanediamine or 1,3-propanediamine. The reaction mixture was stirred for 24 h, after which time the formation of the desired product was evidenced by TLC (eluent: 8:2 dichloromethane/methanol). The solvent was evaporated and the excess of diamine was removed by extraction with dichloromethane and water. The organic layer was concentrated and the residue was purified by column chromatography and/or recrystallization. Yields: (a) 58%, (b) 52%, (c) 46%, (d) 44%, (e) 60%, (f) 53%, (g) 47%, (h) 56%, (i) 48%, and (j) 35%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Stage #1: 1,12-dodecandiol With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: propyl bromide In tetrahydrofuran Reflux; | 3.1.2. 3-(Dodecyloxy)propanoic acid (4) (Scheme 1B) General procedure: NaH (315mg, 13.1mmol) was added in one portion to 1,3-propanediol (19a) (1g, 13.1mmol) and TBAI (16mg, 3mol%) in THF (10mL) at 0°C for 30min. 1-Bromododecane (18a) (2.94g, 11.8mmol) was then added and the reaction was refluxed overnight, then cooled, neutralised with satd NH4Cl and extracted into EtOAc, washed with brine and dried with MgSO4. The product was purified by flash column chromatography; CH2Cl2 gave foreruns, and then elution with EtOAc/CH2Cl2 (5:95) gave 3-(dodecyloxy)propan-1-ol (20a) (1.06g, 31%) as a colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: cyclododecanone With maleic anhydride; dihydrogen peroxide In water at 46 - 49℃; for 22h; Stage #2: With hydrogen In methanol; water at 200℃; for 27h; Autoclave; Inert atmosphere; | 8 Example 8: Reduction of Crude BV product in water and methanol at 2500psig [00128] A mixture of 60 crude BV product, 24 g methanol, 22 g water and 5 g of 2% Ru on carbon catalyst containing 6% Re and 1.4% Sn were charged to a 300 mL Stainless Steel autoclave containing a thermocouple, cooling coil, baffle and stirrer. The BV product contained 39.4 wt% maleic acid, 29.3 wt% LLON, 1.9 wt% 12- hydroxydodecanoic acid, 3.5 wt% 1,12-dodecanedioic acid, 3.4 wt% mono methyl ester of 1,12-dodecandioic acid, and 12.5 wt% water. The vessel was flushed first with nitrogen followed by hydrogen, and pressurized to 2500psig with hydrogen. Stirring at 1800 rpm was commenced and the reactor was heated to 200°C. The hydrogenation was run for 27 hr. Analysis of the product showed a combined 99.6% conversion of LLON, DDDA and HDDA with 86.7% molar% selectivity to C12LD. Also produced was 1-undecanol (3.5 molar%) along with un-reacted 12- hydroxydodecanoic acid (0.6 molar%) and methyl 12-hydroxydodecanoate (2.4 molar%). The ratio of hydrogenolysis products to C12LD was 0.055. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: cyclododecanone With maleic anhydride; dihydrogen peroxide In water at 46 - 49℃; for 22h; Stage #2: With hydrogen In methanol; water at 195℃; for 24h; Autoclave; Inert atmosphere; | 7 Example 7: Reduction of crude BV product in water and methanol [00127] A mixture of 64.1 g crude BV product, 22 g methanol, 22 g water and 5 g of 2% Ru on carbon catalyst containing 6% Re and 0.9% Sn were charged to a 300 mL Stainless Steel autoclave containing a thermocouple, cooling coil, baffle and stirrer. The BV product contained 39.4 wt% maleic acid, 29.3 wt% LLON, 1.9 wt% 12-hydroxydodecanoic acid, 3.5 wt% 1,12-dodecanedioic acid, 3.4 wt% 12- methyl dodecane of 1,12-dodecandioic acid, and 12.5 wt% water. The vessel was flushed first with nitrogen followed by hydrogen and was pressurized to 2000psig with hydrogen. Stirring at 1800 rpm was commenced and the reactor was heated to 195°C. The hydrogenation was run for 24 hr. Analysis of the product showed a combined 99.8 wt% conversion of LLON, DDDA and HDDA with 88.9% molar selectivity to C12LD. Also produced wasl-dodecanol (6.4 molar%) along with un- reacted methyl 12-hydroxydodecanoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: cyclododecanone With maleic anhydride; dihydrogen peroxide In water at 46 - 49℃; for 22h; Stage #2: With hydrogen In methanol; water at 200℃; for 24h; Autoclave; Inert atmosphere; | 9 Example 9: Reduction of crude BV product in water and methanol at 2000psig [00129] A mixture of 64.1 crude BV product, 24 g methanol, 32 g water, 22 g water and 5 g of 2% Ru on carbon catalyst containing 6% Re and 0.9% Sn were charged to a 300 mL Stainless Steel autoclave containing a thermocouple, cooling coil, baffle and stirrer. The BV product contained 39.4 wt% maleic acid, 29.3 wt% LLON, 1.9 wt% 12-hydroxydodecanoic acid, 3.5 wt% 1,12-dodecanedioic acid, 3.4 wt% mono methyl ester of 1,12-dodecandioic acid, and 12.5 wt% water. The vessel was flushed first with nitrogen followed by hydrogen, and pressurized to 2000psig with hydrogen. Stirring at 1800 rpm was commenced and the reactor was heated to 200°C. The hydrogenation was run for 24 hr. Analysis of the product showed a combined 99.8 wt% conversion of LLON, DDDA and HDDA with 88.8% molar selectivity to C12LD. Also produced was 1-undecanol (6.4 molar%) along with 12- hydroxydodecanoic acid (1.2 molar%) and methyl 12-hydroxydodecanoate (4.9 molar%). The ratio of hydrogenolysis products to C12LD was 0.099. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: cyclododecanone With maleic anhydride; dihydrogen peroxide In water at 46 - 49℃; for 22h; Stage #2: With hydrogen In methanol; water at 197℃; for 27h; Autoclave; Inert atmosphere; | 10 Example 10: Reduction of crude BV product in water and methanol [00130] A mixture of 54.8 g crude BV product, 26 g methanol, 30 g water and 5 g of 2% Ru on carbon catalyst containing 6% Re and 1.2% Sn were charged to a 300 mL Stainless Steel autoclave containing a thermocouple, cooling coil, baffle and stirrer. The BV product contained 39.4 wt% maleic acid, 29.3 wt% LLON, 1.9 wt%, 12-hydroxydodecanoic acid, 3.5 wt% 1,12-dodecanedioic acid, 3.4 wt% methyl 12-hydroxydodecanoate, and 12.5 wt% water. The vessel was flushed first with nitrogen followed by hydrogen, and pressurized to 2000psig with hydrogen. Stirring at 1800 rpm was commenced and the reactor was heated to 197°C. The hydrogenation was run for 27 hr. Analysis of the product showed a combined 99.9 wt% conversion of LLON, DDDA and HDDA with 78% molar selectivity to C12LD. Also produced was 1-dodecanol (2.8 molar%) along with un-reacted 12- hydroxydodecanoic acid (2.5 molar%) and methyl 12-hydroxydodecanoate (8.6 molar%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00131] A mixture of 20 g (0.087 mole) 1 ,12-dodecandioic acid, 32 g methanol, 18 g water and 5 g of 5% Ru on carbon catalyst containing 1% Sn are was charged to a 300 mL Stainless Steel autoclave containing a thermocouple, cooling coil, baffle and stirrer. The vessel was flushed first with nitrogen followed by hydrogen, and pressurized to 2500psig with hydrogen. Stirring at 1800 rpm was commenced and the reactor was heated to 230C. The hydrogenation was run for 22 hr. Analysis of the product showed a 98.4 wt% conversion of DDDA with 30.7% molar selectivity to C12LD. Also produced was 1-dodecanol (1.8 molar%) along with the intermediate 12-hydroxydodecanoic acid (14.4 molar%) and the mono methyl ester of 1,12-dodecanedioic acid (38 molar%). It can be seen from the low molar yield to C12LD, the un-reacted intermediate 12-hydroxydodecanoic acid and mono methyl ester of 1 ,2-dodecanedioic acid that the absence of Re had a dramatic effect on the reduction rate to C12LD. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dicarbonylacetylacetonato rhodium (I); N-(3-diphenylphosphanylbenzoyl)guanidine; hydrogen In dichloromethane at 40℃; for 29h; Autoclave; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hydrogen In acetic acid methyl ester; isopropyl alcohol at 45℃; for 3h; Autoclave; | 52 Example 52: A 48.0g solution consisting of 2.53g 1,12-dodecadial, 1.43g 12-oxo- dodecanol, 2.34g cyclododecane, 4.8g methyl acetate with the balance isopropanol is charged to the autoclave described in Example 50 at 15°C. The autoclave is pressure tested at 500psig with slow stirring. The residual nitrogen is removed with two purges of 200psig hydrogen without stirring at 15°C. The autoclave is warmed to 45°C and 900 RPM and stirring commences at 400psig. The hydrogenation is run for 3hrs followed by depressurization to the ambient pressure and nitrogen purging. The product is filtered through Celite filter aid under vacuum to recover approximately 41.7g solution and 8.9g rinse. GC analysis shows complete conversion of 1,12- dodecadial and 12-oxo-dodecanol to 3.56g 1,12-dodecanediol in 89% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogen In isopropyl alcohol at 15 - 45℃; for 3h; Autoclave; | 28 Example 28 (Preparation of 1,12-dodecanediol): About 5g 1,12-dioxo-dodecane (prepared according to Example 24) in about 43 g isopropanol is charged to the autoclave described in Example 26 at 15 °C. The autoclave is pressure tested at SOOpsig with slow stirring. The residual nitrogen is removed with two purges of 200psig hydrogen without stirring at 15°C. The autoclave is warmed to 45°C and 900 RPM and stirring commences at 400psig. The hydrogenation is run for 3hrs followed by depressurization to the ambient pressure and nitrogen purging. The product is filtered through Celite filter aid under vacuum to recover approximately 41.7g solution and 8.9g rinse. GC analysis shows complete conversion of 1,12-dioxo-dodecane to 1,12-dodecanediol in 90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With toluene-4-sulfonic acid In 1,4-dioxane at 160℃; for 0.833333h; | 2 4.1.2. Tetramethylene-1,4-diyl-bis-(3,4,5-trihydroxybenzoate) (8) General procedure: Gallic acid 1 (3.3 mmol, 566 mg), 1,4-butanediol (1.1 mmol, 100 mg) and a catalytic amount of p-toluensulfonic acid were dissolved in dioxane (5 mL) in a distillation system. The mixture was heated at 160 °C distilling the solvent which is continuously refilled until the reaction was completed. The reaction mixture was allowed to reach room temperature and then was cooled by a water-ice bath to give a precipitate that was filtered and washed with gently quantities of diethyl ether to give 305 mg (70%) of 8 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.3% | With sulfuric acid In toluene Reflux; Dean-Stark; | 10 4.10. 12-(Anthracen-9-yloxy) dodecan-1-ol (18) In a 2 L flask equipped with a Dean-Stark water separator, 12.0 g anthrone (61.7 mmol, 1 equiv) was dissolved in 1 L toluene. 1,12-dodecanediol (125 g, 617 mmol, 10 equiv) and 2.5 mL sulfuric acid (≥95%) were added and the solution was heated to reflux. The reaction mixture was stirred overnight and the reaction was monitored by thin layer chromatography. After cooling, the precipitated excess of 1,12-dodecanediol was removed by filtration and the filtrate was washed with a saturated aqueous sodium bicarbonate solution (300 mL) and water (300 mL). The combined aqueous phases were extracted with diethyl ether, the combined organic phases were dried over magnesium sulfate and concentrated in vacuo. To obtain purified 12-(anthracen-9-yloxy) dodecan-1-ol 18 (17.7 g, 75.3 %) as a yellow-orange oil, the dried mixture was purified via chromatography on silica (eluent: CH2Cl2); Rf (CH2Cl2) 0.13; 1H NMR (400 MHz, CDCl3): δ (ppm)=1.26-1.51 (m, 14H, CH2CH2CH2), 1.54-1.62 (m, 2H, CH2CH2CH2), 1.68 (quin, J=7.5 Hz, 2H, CH2CH2CH2), 2.07 (quin, J=7.4 Hz, 2H, CH2CH2OH), 3.65 (t, J=6.7 Hz, 2H, CH2OH), 4.21 (t, J=6.7 Hz, 2H, AnthrOCH2), 7.45-7.52 (m, 4H, CHCHCHCH), 7.98-8.03 (m, 2H, CHCCHCH), 8.22 (s, 1H, CCHC), 8.29-8.34 (m, 2H, CCCHCH); 13C NMR (100 MHz, CDCl3): δ (ppm)=25.8 (CH2), 26.3 (CH2), 29.5 (CH2), 29.6 (CH2), 29.7 (CH2), 30.7 (CH2), 32.8 (CH2), 63.1 (CH2), 76.2 (CH2), 122.0 (CH), 122.5 (CH), 124.8 (C), 125.0 (CH), 125.5 (CH), 128.4 (CH), 132.5 (C), 151.6 (C); LC-MS (m/z) 379.20 [MH]+; HRMS (m/z for [MH]+) calcd: 379.2633; found: 379.2633. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium hydroxide In ethanol for 18h; Reflux; | 4 The 175.7g2,6- methyl-tert-butyl-bromo anisole and 171.2g1,12- twelve diol being added to 5L three-necked flask, again flask 2L ethanol solvent and 22.6g hydroxide sodium. The reaction mixture was heated at reflux for 18 hours, the heating means is removed, the reaction solution was cooled to 25 . The resulting solid was removed under reduced pressure The solvent was dissolved into 1.5L ether, extracted three times with 1L of distilled water again, the organic layer was extracted once again after the organic layer twice with a dilute hydrochloric acid, dilute aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate 24 hours. The drying agent was removed by filtration pressurized solvent was distilled off the crude solid by column chromatography (developing solvent, chloroform, methanol) to give pure 1,12 glycol mono - (3,5-di-t-butyl, 4 - methoxy) anisole 146.4g, 60% yield. |
60% | With sodium hydroxide In ethanol for 18h; Reflux; | 4 Example 4 175.7 g of 2,6-di-t-butyl p-bromomethylanisole and 171.2 g of 1,12-dodecanediol were added to a 5 L three-necked flask,The flask was further charged with 2 L of absolute ethanol solvent and 22.6 g of sodium hydroxide.After the reaction mixture was heated under reflux for 18 hours, the heating apparatus was removed and the reaction solution was cooled to 25 ° C.The solvent was removed under reduced pressure, and the resulting solid was dissolved in 1.5 L of diethyl ether, extracted three times with 1 L of distilled water,The organic layer was again extracted twice with dilute sodium bicarbonate solution and dilute hydrochloric acid solution, and the organic layer was dried over anhydrous magnesium sulfate for 24 hours.The drying agent was removed by filtration pressurized solvent was distilled off the crude solid by column chromatography (developing solvent, chloroform, methanol) to give pure 1,12 glycol mono - (3,5-di-t-butyl, 4 - methoxy) anisole 146.4g, 60% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With pyridine In tetrahydrofuran; acetone at 20℃; for 6h; Cooling with ice; | 1.2 Example 1 Preparation of compound C4 (2) 0.01 mol of 1,12-dodecanediol,0.06 mol of pyridine was added to 40 ml of acetone,20 ml of a THF solution of 0.026 mol of 2,4-dichlorophenoxyacetyl chloride prepared as described above was added dropwise slowly under ice-cooling,After completion of the dropwise addition,The reaction was stirred at room temperature,Liquid chromatography monitoring to the end of the reaction,With 6h,Decompression,The residue was dissolved in methylene chloride,0.5mol / L sodium hydroxide solution,Extraction to get the oil layer,The oil layer was washed with water until neutral,Desolvation,Recrystallization from methanol,The product,Yield 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.4 g | With thionyl chloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; Cooling with ice; | 3 At 0 deg.] C, dry conditions, the 1,12-dodecanediol (15 g, 74.1 mmol) and diisopropylethyl amine (62.0 ml, 355.9 mmol, 4.8 eq.) Was dissolved in dichloromethane (1500mL), under stirring slowly added dropwise to this solution, a solution of thionyl chloride in methylene chloride (375mL methylene chloride, thionyl chloride containing 10.8 ml, 148.3 mmol, 2 eq.), after the dropwise addition stirring was continued at the room temperature of the reaction for one hour. Then the reaction mixture was added water to quench the reaction, then brine, to give a dark brown aqueous phase was extracted twice with dichloromethane, organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to liquid-separation the residue residue was filtered through a short column of silica gel to give the macrocyclic cyclic sulfite crude product (18.4 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: 1,12-dodecandiol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #2: ethyl bromide With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide at 0℃; | 2-(Dodecyloxy)ethanol (10a) General procedure: Ethanediol (1.1 mL, 20.00 mmol) was dissolved in 200 mL anhydrous DMF, NaH (480 mg, 12.0 mmol) was added in at 0°C. The mixture was warmed up to room temperature and stirred for 30 min. Then 1-bromododecane (2.4 mL, 10.00 mmol), TBAI (369 mg, 1.0 mmol) were added in at 0 °C,kept stirring overnight. The reaction mixture was diluted with 20 mL methanol, then washed with 1 N HCl solution, water, saturated aqueous solution of NaHCO3 and brine, successively.The organic phase was dried over Na2SO4, filtered, and then concentrated. The crude mixture was purified by column chromatography (petroleum ether-EtOAc 30 : 1) on silica gel to afford 10a as a colorless oil (1.12 g, 49%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,4-diaza-bicyclo[2.2.2]octane; triethylamine In tetrahydrofuran at 25℃; for 10h; | 7 Preparation of dodecanediol monomethyl dicarboxylate furan dicarboxylate 8.1 g of dodecanediol, 5.56 mL of triethylamine and 449 mg of 1,4-diazabicyclo [2.2.2] octane were dissolved in 150 mL of tetrahydrofuran, and 3.77 g of monomethyl methimidocarboxylate was added, 25 ° C for 10 h after the reaction to remove tetrahydrofuran by steam. After adding 25 mL of dichloromethane, the filtrate was filtered and the filtrate was dried to give the dodecanediol monomethyl furan dicarboxylate represented by the formula (5) in a yield of 96% |
With 1,4-diaza-bicyclo[2.2.2]octane; triethylamine In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With hafnium(IV) trifluoromethanesulfonate; In toluene; at 110℃; for 24h;Inert atmosphere; | A 2000 mL two-necked,round-bottomed flask, equipped with a Dimroth condenser and a magnetic stirring bar, wascharged with <strong>[142-45-0]acetylenedicarboxylic acid</strong> (345 mg, 3.0 mmol) and 1,12-dodecanediol (618 mg,3.0 mmol). The flask was evacuated and backfilled with nitrogen. Toluene (dry, 600 mL) andHf(OTf)4 (232 mg, 0.30 mmol) were added to the flask, and the mixture was reacted at 110 Cwith stirring for 24 h. After cooling to room temperature, silica gel (0.7 g) was added to theflask and volatiles were removed by a rotary evaporator. The silica gel was collected andcharged with a column. 1,6-Dioxacyclooctadec-3-yne-2,5-dione (7h, 431 mg, 51%) wasobtained as colorless oil after purification by column chromatography on silica gel (Ultra PureSilica Gel; eluent: hexane:EtOAc = 19:1). 7h: 1H NMR (400 MHz, CDCl3) delta 4.29-4.33 (m, 4H),1.67-1.75 (m, 4H), 1.36-1.51 (m, 8H), 1.25-1.36 (m, 8H). 13C NMR (101 MHz, CDCl3) delta 151.9,74.9, 67.9, 29.3, 28.8, 28.3, 27.3, 26.4. HRMS (APCI, positive) m/z calcd for C16H25O4+ [M +H]+: 281.1747, found: 281.1742. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Stage #1: 3α,11α-epoxy-3,4,5,5aα,6,7,8,8a,9,11,11a-undecahydro-3β,6α,9α-trimethylfurano<3,4-j><1,2>benzodioxepin-9β-carboxylic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; Stage #2: 1,12-dodecandiol In dichloromethane at 20℃; | 2 4.2.5. General procedure for the preparation of compounds 6a-l General procedure: Compound 5 (1mmol) was dissolved in 5mL of DCM, EDCI (1.2mmol, 1.2 equiv) and TEA (0.1mmol, 0.1 equiv) were added to the solution respectively. The mixture was stirred for 1h at room temperature then diol was added to the solution. After stirring for 10h, the mixture was diluted with water (5mL) and extracted with EtOAc (3×20mL), then the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification was carried out through column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With Candida antarctica lipase immobilized on acrylic resin; In toluene; for 9h;Heating; Enzymatic reaction; | General procedure: <strong>[141-22-0]Ricinoleic acid</strong> 1 (R=H) (13mmol) and an excess of diol 2a or 2d (50mmol) was esterified in toluene under vacuum azeotropic distillation for 9h in the presence of C. antarctica lipase. The reaction mixture was cooled, the lipase was filtered off and the solvent was removed under reduced pressure. Diethyl ether was added to the residue, the excess of diol 2 was filtered off and the ether phase was evaporated under vacuum to yield the mixture of esters having about 72% of monoester and 18% of diester (HPLC analysis). The mixture was purified by flash chromatography with silica gel using petroleum ether/diethyl ether/acetic acid: 2/1/0.01 as eluent to give the pure monoesters 3a (n=10) or 3d (n=12). 4.3.1.1.1 Monoester 3a (n=10) 2.24g (60%). FTIR numax (cm-1) 3258 (OH), 3174, 3070 (CH=CH), 2956, 2852, 1735 (carbonylic ester), 1461, 1260, 1177, 1051, 883, 796, 721. 1H NMR (CDCl3, 500MHz) delta ppm 5.56 (1H, m, CH2-CH=CH-CH2-CH(OH)), 5.41 (1H, m, CH2-CH=CH-CH2-CH(OH)), 4.06 (2H, t, J3=7.0Hz, CH2-CH2-O-CO), 3.64 (2H, t, J3=6.5Hz, CH2-OH), 3.62 (1H, m, CH=CH-CH2-CH(OH)), 2.29 (2H, t, J3=7.5Hz, O-CO-CH2-CH2), 2.21 (2H, t, J3=7.0Hz, CH=CH-CH2-CH(OH)), 2.05 (2H, q, J3=7.0Hz, CH2-CH=CH-CH2-CH(OH)), 1.62, 1.47, 1.30 (36H, m, CH2), 0.89 (3H, t, J3=7.0Hz, CH3-CH2). 13C NMR (CDCl3, 125MHz) delta ppm 174.54 (CO), 133.90 (CH2-CH=CH-CH2-CH(OH)), 125.74 (CH2-CH=CH-CH2-CH(OH)), 72.04 (CH=CH-CH2-CH(OH)), 64.92 (CH2-OH), 63.57 (CH2-CH2-O-CO), 35.88 (CH=CH-CH2-CH(OH)), 34.91 (O-CO-CH2-CH2), 27.37 (CH2-CH=CH-CH2-CH(OH)), 37.37 (CH=CH-CH2-CH(OH)-CH2-CH2), 32.36, 30.11, 30.00, 29.89, 29.72, 29.63, 29.15, 26.43, 26.24, 25.51, 23.14 (CH2), 14.60 (CH3-CH2). MS (ESI) positive mode (m/z): calcd for C28H54O4, [M+H]+ 455.4086, found [M+H]+ 455.4036 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: pellynol O With ozone In dichloromethane at -78℃; for 0.0166667h; Stage #2: With sodium tetrahydroborate In dichloromethane at 25℃; for 1h; | 3.4. Ozonolysis of 1-3 General procedure: Solutions of 1-3 (0.5mg each) in CH2Cl2 (1mL) were treated with O3 for 1 min at-78°C, respectively. After added NaBH4 (0.5mg), the reaction mixtures were stirred for 1 h at room temperature (25°C).20 The crude products were concentrated and subjected to LC-MS analysis without further separation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With hafnium tetrakis(trifluoromethanesulfonate) In toluene at 110℃; for 16h; | 3 4.2 General procedure synthesis of macrodiolides General procedure: Dicarboxylic acid (0.2 mmol, 1.0 equiv.) and 1Z,5Z-dienediol (0.2 mmol, 1.0 equiv.) were dissolved in toluene (40 mL, 5 mM). Then Hf(OTf)4 (0.02 mmol, 0.1 equiv.) was added to the solution and the reaction mixture heated to 110 °C. The reaction mixture was stirred at this temperature for 16-18 h. After cooling to room temperature, silica gel (~1 mL) was added and the slurry was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether/EtOAc (20/1)) to afford the desired product as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With hafnium tetrakis(trifluoromethanesulfonate) In toluene at 110℃; for 16h; | 3 4.2 General procedure synthesis of macrodiolides General procedure: Dicarboxylic acid (0.2 mmol, 1.0 equiv.) and 1Z,5Z-dienediol (0.2 mmol, 1.0 equiv.) were dissolved in toluene (40 mL, 5 mM). Then Hf(OTf)4 (0.02 mmol, 0.1 equiv.) was added to the solution and the reaction mixture heated to 110 °C. The reaction mixture was stirred at this temperature for 16-18 h. After cooling to room temperature, silica gel (~1 mL) was added and the slurry was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether/EtOAc (20/1)) to afford the desired product as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With hafnium tetrakis(trifluoromethanesulfonate) In toluene at 110℃; for 16h; | 3 4.2 General procedure synthesis of macrodiolides General procedure: Dicarboxylic acid (0.2 mmol, 1.0 equiv.) and 1Z,5Z-dienediol (0.2 mmol, 1.0 equiv.) were dissolved in toluene (40 mL, 5 mM). Then Hf(OTf)4 (0.02 mmol, 0.1 equiv.) was added to the solution and the reaction mixture heated to 110 °C. The reaction mixture was stirred at this temperature for 16-18 h. After cooling to room temperature, silica gel (~1 mL) was added and the slurry was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether/EtOAc (20/1)) to afford the desired product as a colorless oil. |
59% | With hafnium tetrakis(trifluoromethanesulfonate) In toluene at 110℃; for 16h; | General procedure synthesis of macrodiolides. General procedure: Dienedicarboxylic acid (0.2 mmol, 1.0 equiv.) and diol (0.2 mmol, 1.0 equiv.) were dissolved in toluene (40 mL, 5 mM). Then Hf(OTf)4 (0.015 g, 0.02 mmol, 0.1equiv.) was added to the solution and the reaction mixture heated to 110 °C for 16-18 h. After cooling to room temperature, silica gel (~0.7 g) was added and the slurry was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether/EtOAc (15/1)) to afford the desired product as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With hafnium tetrakis(trifluoromethanesulfonate) In toluene at 110℃; for 16h; | 3 4.2 General procedure synthesis of macrodiolides General procedure: Dicarboxylic acid (0.2 mmol, 1.0 equiv.) and 1Z,5Z-dienediol (0.2 mmol, 1.0 equiv.) were dissolved in toluene (40 mL, 5 mM). Then Hf(OTf)4 (0.02 mmol, 0.1 equiv.) was added to the solution and the reaction mixture heated to 110 °C. The reaction mixture was stirred at this temperature for 16-18 h. After cooling to room temperature, silica gel (~1 mL) was added and the slurry was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether/EtOAc (20/1)) to afford the desired product as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In diethyl ether at 20℃; for 1h; Inert atmosphere; | 2.5. Preparation of 1,12-diazidododecane In a two-necked round bottom flask equipped with a magnetic stirring and a nitrogen flow, 6.0 mL of Et3N (45.5 mmol) followed by 3.9 mL (50.0 mmol) of mesyl chloride were added in a dropwise manner to a solution of dodecane-1,12-diol (22.7 mmol) in 50 mL of diethyl ether. After stirring for 1 h at room temperature, the reaction mixture was washed with water and dried over MgSO4. The solvent was then evaporated to afford 1,12-dimesyl-dodecane in90-93% yields. Then, to a solution of 1,12-dimesyl-dodecane(61 mmol of mesylate groups) in 140 mL of DMF, was added NaN3(91.5 mmol). After stirring for 24 h at 75 C, the reaction mixture was washed with 50 mL of water, extracted with diethyl ether(6 50 mL) and dried over MgSO4. The solvent was then evaporatedto afford 1,12-diazido-dodecane in 88-90% yields. 1H NMR(300 MHz, CDCl3, δ/ppm): 1.26-1.61 (m, 20H, CH2), 3.25 (t, 4H,CH2-N3). 13C NMR (75 MHz, CDCl3, δ/ppm): 25.1; 25.7; 27.8, 28.5,30.7, 51.4. IR: ν = 2091 cm-1 (s, νN3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In cyclohexane; at 95℃; for 8h;Inert atmosphere; | To a 500 ml single-mouth bottle, 10.1 g (0.05 mol) of 1,12-dodecanediol and 55.6 g (0.2 mol) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid were added. 0.505 g of p-toluenesulfonic acid, 200 ml of cyclohexane, under nitrogen protection, stirring at 95 C for 8 h, the rotation speed was set to 100 r / min, water was separated by a water separator and the reaction end point was determined, and the reaction was ended, using saturated sodium hydrogencarbonate The aqueous solution was titrated to pH=8.00, and the reaction solution was titrated with ethyl acetate. The extraction volume ratio of the ethyl acetate to the reaction solution was 1:1, and the ethyl acetate layer was separated by liquid separation, and the acetic acid was repeatedly washed with distilled water. The ester layer is separated and separated until the liquid layer is distilled to pH=7.00, and the ethyl acetate layer is evaporated to remove ethyl acetate to obtain a colorless transparent oily fluid. The drying fluid can obtain a colorless transparent sticky solid. Hindered phenol damping modifier. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; | 4.8. General Synthetic Procedure for 9g-9i General procedure: A mixture of cinnamic acid (6.30 mmol), EDCI (7.50 mmol), DMAP (0.60 mmol), and anhydrous dichloromethane (20 mL) was stirred to dissolve, then alkane-diol (3 mmol) was added and stirred at room temperature for 12 h. The mixture solution was filtered under reduced pressure. After that, the residue was washed with dichloromethane and water successively, subsequently, purified by preparative TLC eluted with petroleum ether/ethyl acetate = 5:1 to give pale white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pentafluorobenzoylchloride; triethylamine In toluene at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With pentafluorobenzoylchloride; triethylamine In toluene at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: 1,12-dodecandiol With potassium hydroxide at 135℃; for 3h; Inert atmosphere; Large scale; Stage #2: acetylene at 155℃; for 17h; Large scale; | 3 Example 3: Synthesis of 1,12-dodecanediol divinyl ether (3DVE) Into the same reaction vessel as in Example 1, 0.23 kg (4.1 mol) of potassium hydroxide and 3.96 kg (19.6 mol) of 1,12-dodecanediol (manufactured by FUJIFILM Wako Chemical Corporation) that had previously dissolved by heating were charged, and nitrogen was purged inside the vessel.After nitrogen purge, the temperature inside the vessel was raised to 135° C. and stirring was performed at 250 rpm. The pressure inside the vessel was gradually reduced to 20 kPaA, and bubbling with 0.1 NL/min nitrogen was performed for 3 hr from the liquid sampling line. Through the above operation, 0.09 kg of a distillate including water as the main component was taken out. Thus, potassium alkoxide derived from 1,12-dodecanediol was obtained.Then, the temperature in the vessel was raised to 155° C., and the inside of the vessel was purged with acetylene while stirring at 420 rpm. Acetylene was continuously supplied, the inside of the vessel was kept at 0.03 MPaG and 155° C., and the reaction was performed for 17 hr. As a result of gas chromatography analysis of the reaction solution, the conversion rate was 99% or more, and the selectivity was 94%. The reaction rate in this case was calculated to be 52 g/L·hr, and the production rate in reaction step was calculated to be 44 g/L·hr.This reaction solution was subjected to filtration under pressure at 120° C. and a nitrogen pressure of 0.1 MPaG by using the same filter cloth as in Example 1 to separate a catalyst. The potassium concentration in the filtrate was 0.2% by mass. Moreover, simple distillation of the filtrate was performed under a reduced pressure of 0.06 kPaA to obtain 3.34 kg (13.1 mol) of 1,12-dodecanediol divinyl ether (hereinafter referred to as 3DVE). The obtained 3DVE had a purity of 99% or more, a melting point of 27° C. and a yield of 67%. In addition, the required energy at the distillation was calculated as 0.3 MJ per 1 kg of 3DVE. |
67% | Stage #1: 1,12-dodecandiol With potassium hydroxide In neat (no solvent) at 135℃; for 3h; Inert atmosphere; Stage #2: acetylene In neat (no solvent) at 155℃; for 17h; Inert atmosphere; | 3 Example 3: Synthesis of 1,12-Dodecanediol Divinyl Ether (3DVE) Into the same reaction vessel as in Example 1, 0.23 kg (4.1 mol) of potassium hydroxide and 3.96 kg (19.6 mol) of 1,12-dodecanediol (manufactured by FUJIFILM Wako Chemical Corporation) that had previously dissolved by heating were charged, and nitrogen was purged inside the vessel. After nitrogen purge, the temperature inside the vessel was raised to 135° C. and stirring was performed at 250 rpm. The pressure inside the vessel was gradually reduced to 20 kPaA, and bubbling with 0.1 NL/min nitrogen was performed for 3 hr from the liquid sampling line. Through the above operation, 0.09 kg of a distillate including water as the main component was taken out. Thus, potassium alkoxide derived from 1,12-dodecanediol was obtained. Then, the temperature in the vessel was raised to 155° C., and the inside of the vessel was purged with acetylene while stirring at 420 rpm. Acetylene was continuously supplied, the inside of the vessel was kept at 0.03 MPaG and 155° C., and the reaction was performed for 17 hr. As a result of gas chromatography analysis of the reaction solution, the conversion rate was 99% or more, and the selectivity was 94°. The reaction rate in this case was calculated to be 52 g/L·hr, and the production rate in reaction step was calculated to be 44 g/L·hr. This reaction solution was subjected to filtration under pressure at 120° C. and a nitrogen pressure of 0.1 MPaG by using the same filter cloth as in Example 1 to separate a catalyst. The potassium concentration in the filtrate was 0.2% by mass. Moreover, simple distillation of the filtrate was performed under a reduced pressure of 0.06 kPaA to obtain 3.34 kg (13.1 mol) of 1,12-dodecanediol divinyl ether (hereinafter referred to as 3DVE). The obtained 3DVE had a purity of 99% or more and a yield of 67%. The results are shown in Table 1. |
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