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CAS No. : | 60-33-3 | MDL No. : | MFCD00064241 |
Formula : | C18H32O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OYHQOLUKZRVURQ-HZJYTTRNSA-N |
M.W : | 280.45 | Pubchem ID : | 5280450 |
Synonyms : |
Octadecadienoic acid (all cis-9,12);C18:2 (all cis-9,12) Fatty acid
|
Chemical Name : | (9Z,12Z)-Octadeca-9,12-dienoic acid |
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.72 |
Num. rotatable bonds : | 14 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 89.46 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -3.05 cm/s |
Log Po/w (iLOGP) : | 4.14 |
Log Po/w (XLOGP3) : | 6.98 |
Log Po/w (WLOGP) : | 5.88 |
Log Po/w (MLOGP) : | 4.47 |
Log Po/w (SILICOS-IT) : | 5.77 |
Consensus Log Po/w : | 5.45 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -5.05 |
Solubility : | 0.00249 mg/ml ; 0.00000887 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -7.58 |
Solubility : | 0.00000742 mg/ml ; 0.0000000264 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -4.67 |
Solubility : | 0.00593 mg/ml ; 0.0000211 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.1 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
91% | With lithium aluminium tetrahydride In tetrahydrofuranReflux | Lithium aluminum hydride (2.73 g, 72 mmol) was suspended in tetrahydrofuran (THF, 190 mL) cooled at 4° C. Linoleic acid (10 g, 36 mmol) was added dropwise to the suspension, and the resulting mixture was stirred for 10 minutes. Then, the mixture was refluxed overnight with heating on an oil bath. After cooling the mixture, 1 mol/L aqueous sodium hydroxide (100 mL) was added to terminate the reaction. Then, the reaction mixture was diluted with ethyl acetate (100 mL), and filtered, and the filtrate was washed with saturated aqueous sodium hydrogencarbonate. Then, the organic layer was collected, and dried over anhydrous sodium sulfate. The organic layer was filtered, and the solvent was evaporated by using a rotating evaporator to obtain a crude product. The crude product was purified by silica gel chromatography (elution solvent, hexane:ethyl acetate, continuous gradient) to obtain 9z,12z-octadecadien-1-ol (8.68 g, 32.6 mmol) as colorless oil. Yield was 91percent. Proton nuclear magnetic resonance (1H NMR, 500 MHz) data of 9z,12z-octadecadien-1-ol δ=0.88 (t, 3H), 1.25-1.36 (m, 16H), 1.53-1.58 (m, 2H), 2.02-2.06 (m, 4H), 2.76 (t, 2H), 3.62 (t, 2H), 5.29-5.40 (m, 4H) |
28.2 g | With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran; toluene at 0 - 20℃; Inert atmosphere | A 1 L glass reactor fitted with an argon inlet was purged with dry argon, and charged with of linoleic acid (30 g, 107 mmol) and THF (320 mL). The reaction mixture was cooled to 0° C. with acetone-dry-ice mixture. While maintaining the reaction temperature below 0° C., 73 mL of sodium his (2-methoxyethoxy) aluminum hydride solution in methylbenzene (60percent wt/vol) was added drop wise. After the completion of addition, the reaction mixture was incubated at ambient temperature for 2 hours. After reaction, the reaction mixture was cooled to 0° C. To the reaction mixture, a saturated sodium sulfate solution (prepared by dissolving 5.75 g Na2SO4 in 7.85 mL of water) was added drop wise over a period of more than 45 minutes; then, 130 mL of ethyl acetate was added drop wise to the reaction over a period of 30 minutes, with violent stir. The reaction mixture was filtered and the residues were washed with ethyl acetate. The organic layers were combined and concentrated. The resulting product was dissolved in 90 mL of ethyl acetate and washed twice with 45 mL of water, and dried over anhydrous sodium sulfate. Then, the solution was filtered, the organic layer was concentrated to remove the organic solvent with a vacuum pump, resulted in 28.8 g of product 2. |
28.8 g | With sodium bis(2-methoxyethoxy)aluminium dihydride In toluene at 0 - 20℃; for 2 h; | 30 g of linoleic acid (Reactant 1) and THF (320 ml) were added to the reactor. 73 ml of a red aluminum solution (60percent wt/vol) in toluene was slowly added dropwise to the reactor, keeping the temperature at about 0°C during the addition. After the addition was completed, the reaction was performed at room temperature for 2 hours.The solution was cooled to 0°C and saturated sodium sulfate solution was slowly added.After the addition was completed, 130 ml of ethyl acetate was added dropwise over 30 minutes.Stir vigorously. The reaction solution was filtered and the solid was washed with ethyl acetate. The organic phases were combined and concentrated. The product was dissolved in 80 ml of ethyl acetate, washed twice with water, and dried over anhydrous sodium sulfate. filter,The organic phase was concentrated to remove the solvent to give product 2 (28.8 g). |
28.8 g | With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran at 0 - 20℃; for 2 h; | 30 g of linoleic acid (Reaction 1) and THF (320 ml) were charged to the reactor. 73 ml of a Sodium bis(2-methoxyethoxy)aluminium hydride (trade name Red-Al) solution (60percent wt/vol) in toluene solution was slowly added dropwise to the reactor, and the temperature was maintained at about 0 ° C during the dropwise addition. After the completion of the dropwise addition, the reaction was carried out for 2 hours at room temperature. The solution was cooled to 0 ° C and a saturated sodium sulfate solution was slowly added. After the dropwise addition was completed, 130 ml of ethyl acetate was added dropwise within 30 minutes, and vigorously stirred. The reaction mixture was filtered, solid was washed with ethyl acetate, and then organic phases were combined and concentrated. The product was dissolved in 80 ml of ethyl acetate, washed twice with water and dried over anhydrous sodium sulfate. Filtration and concentration was carried out for the organic phase to remove solvent, and obtain Intermediate 2 (28.8 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.4% | at 50℃; for 72 h; Inert atmosphere | In a typical experiment, 2.7 mg of G2 (3.2 μmol) was dissolved in 10 g of linoleic(35.7 mmol) in a 100 ml glass flask under an N2 atmosphere. The reaction mixture wasstirred and heated at 50C in an oil bath for 72 hours. The reaction mixture wasdissolved in small amount of CHCl3 and precipitated in hexane. The mixture was thenfiltrated and the resulting solid was washed with hexane to give a white powder:Octadec-9-enedioic acid in a 23percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With oxalyl dichloride In dichloromethane at 20℃; | |
99% | With oxalyl dichloride | |
92% | With oxalyl dichloride In dichloromethane at 0 - 20℃; for 4h; |
90% | With thionyl chloride; N,N-dimethyl-formamide In cyclohexane at 5 - 20℃; for 24h; Inert atmosphere; | 1.2 Example 1 Step 2 Preparation of Linoleoyl Chloride A) Add 5 parts DMF (dimethyformamide) to 12,000 parts chilled (5 °C) cyclohexane and 3000 parts chilled (5 °C) linoleic acid and stir under a nitrogen flow of 0.2 - 0.4 L/min in an ice bath. B) Add chilled (5 °C) thionyl chloride, SOCl2, dropwise at 3 to 4 mL/min. C) After all of the thionyl chloride is added, allow the ice bath to come to room temperature and continue stirring under nitrogen flow for 24 hours or until all gas evolution has ceased. D) Decant cyclohexane from tar layer and evaporate under nitrogen to recover clear amber liquid. Store well sealed in glass containers. The product is obtained in a 90%> yield. |
With thionyl chloride | ||
With phosphorus trichloride | ||
With Carbon tetrachloride; phosphorus trichloride | ||
With thionyl chloride; Petroleum ether | ||
With trichlorophosphate In toluene | ||
With oxalyl dichloride; N,N-dimethyl-formamide In benzene Ambient temperature; | ||
With oxalyl dichloride | ||
With oxalyl dichloride for 3h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In benzene for 3h; Ambient temperature; | ||
With oxalyl dichloride In hexane for 3h; Heating; | ||
With oxalyl dichloride In N,N-dimethyl-formamide; benzene at 0℃; for 1h; | ||
With oxalyl dichloride In chloroform for 2h; | ||
With oxalyl dichloride In toluene at 20℃; | ||
With oxalyl dichloride In toluene at 20℃; | ||
With oxalyl dichloride In dichloromethane at 20℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | ||
With thionyl chloride In benzene at 50℃; for 24h; | ||
With thionyl chloride at 40℃; for 1.5h; | 5 In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 9.35 ml (128 mmol) of thionyl chloride, and a water condenser, is placed 24.90 ml (80 mmol) of linoleic acid. Addition of the thionyl chloride is completed with heating to about 40° C. over the course of about 40 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 50 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, (9Z,12Z)-octadeca-9,12-dienoyl chloride | |
With thionyl chloride at 40℃; for 1.5h; Heating / reflux; Neat (no solvent); | 5 In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 9.35ml (128mmol) of thionyl chloϖde, and a water condenser, is placed 24.90ml (80mmol) of lmoleic acid. Addition of the thionyl chloϖde is completed with heating to about 40°C over the course of about 40 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 50 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloϖde, (9Z,12Z)-octadeca-9,12- dienoyl chloride | |
With phosphorus trichloride at 70℃; for 2h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Cooling; | ||
With oxalyl dichloride; N,N-dimethyl-formamide | ||
With oxalyl dichloride In dichloromethane for 0.0833333h; | 1 Example 1; The linoleic acid analog containing an azido group 3 and the linoleic acid analog containing an terminal acetylene group 4 were synthesized as shown in FIG. 1.The synthesis of the acid chloride 1 was done under anhydrous conditions, using DMF as a catalyst. The reaction was fairly quick (~5 min) and observed on TLC by conversion to the methyl ester (quench with MeOH). The acid chloride 2 was then readily converted to either compound 3 or 4 by low temperature addition (-78°C) in the presence of DIEA. | |
With oxalyl dichloride In dichloromethane at 65℃; for 0.0833333h; | ||
With oxalyl dichloride In dichloromethane at 0 - 20℃; for 6h; | 4.11. General procedure for the preparation of 5-O-acyl juglones via acyl chlorides General procedure: To a solution of carboxylic acid (1 equiv) in CH2Cl2, oxalyl chloride (3.1 equiv) was added at 0 °C, and the mixture was stirred at room temperature for 6 h. The solvent was removed to yield crude acyl chloride. A solution of the acyl chloride (1 equiv), juglone (3 equiv) and DMAP (0.1 equiv) in pyridine was stirred at room temperature. After the mixture had been stirred for 3 h, the reaction was quenched by the addition of 1 M aqueous HCl solution. The resulting mixture was extracted with EtOAc. The extract was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography using hexanes/ethyl acetate as the eluent. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 21℃; Inert atmosphere; | ||
With thionyl chloride In benzene at 20℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride In toluene at 0 - 20℃; for 3h; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane at 20℃; for 3h; | General Procedure for Preparation of N-Acylhistamines (N-Acyl-HAs) General procedure: A solution of fatty acid acyl chloride (1.0 mmol), purchased from Tokyo Chemical Industory (Tokyo, Japan), in N,N-dimethylformamide (DMF) (2 mL) was added dropwise to a suspension of histamine dihydrochlolide (2.0 mmol) and Et3N (8 mmol) in DMF (5 mL) cooled in an ice bath. In some cases (i.e., for the C18:1, C18:2 and C20:4 analogues), the acyl chlorides were prepared by reacting the free fatty acids with oxalyl chloride (5 eq, CH2Cl2, r.t., 3 h). The reaction mixture was stirred for 5 h at room temperature. Ice water was added to the mixture and the reaction mix was extracted with CHCl3. The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 : MeOH : aq. NH3=20 : 1 : 0.5) to give the corresponding N-acylhistamine. | |
With thionyl chloride | ||
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0℃; Inert atmosphere; | Synthesis of the Curcumin Derivatives General procedure: For compounds2-4, the corresponding acid chlorides (oleic, linoleic, andlinolenic acid) were prepared by treatment of the acid (1 equiv)in anhydrous dichloromethane and thionyl chloride (1.1 equiv)under nitrogen at 0 °C with a catalytic amount of DMF. Acidchloride was distilled under vacuum and used immediately forthe next step. Curcumin (1 equiv) was dissolved in anhydrouspyridine at 0 °C under nitrogen and treated with different acidchlorides. The reaction mixture was allowed to stir for 2 h atroom temperature and then heated at 60 °C for an additional 2h. After the mixture had been cooled to room temperature,excess pyridine was evaporated under high vacuum. Theresulting residue was subjected to column chromatography.Compounds 5 and 6 were synthesized as describedpreviously.34 The chemical structure of 1-6 is shown in Figure1. | |
With oxalyl dichloride; N,N-dimethyl-formamide In benzene at 20℃; for 2h; | 3.5.1. 4-Methyl-2-thioxothiazol-3(2H)-yl(Z,Z)-9,12-octadecadienoate (3) To a solution of LA (1.0 g, 3.57 mmol) in benzene (10 mL), oxalyl chloride (1.0 mL, 11.7 mmol) andDMF (1 drop) was added at room temperature. The mixture was stirred for 2 h and then evaporatedin vacuo. The residue was dissolved in diethyl ether (3 mL) and the mixture was added to a solutionof 3-hydroxy-4-methyl-2(3H)-thiazolethione (535 mg, 3.64 mmol) and pyridine (2 drops) in diethylether (12 mL). The mixture was stirred for 10 min at room temperature, after which it was filtered andevaporated in vacuo. The residue was purified on a SiO2 column (hexane:EtOAc, 6:1) to yield ester 3 asa bright yellow oil (1.08 g, 74%). 1H-NMR (400 MHz, CDCl3) δ 6.23 (1H, d, J = 1.2 Hz), 5.36 (4H, m),2.76 (2H, t, J = 6.0 Hz), 2.71 (1H, t, J = 8.6 Hz), 2.64 (1H, t, J = 8.0 Hz), 2.16 (3H, d, J = 1.2 Hz), 2.06 (4H,m), 1.82 (2H, m), 1.46 (2H, m), 1.24-1.39 (12H, m), 0.89 (3H, t, J = 6.8 Hz). 13C-NMR (100 MHz, CDCl3) δ 180.85 (C=S), 168.96 (C=O), 136.90 (=C-N), 130.25 (C=), 129.96 (C=), 128.14 (C=), 127.89 (C=), 102.37(=C-S), 31.53 (CH2), 31.36 (CH2), 29.56 (CH2), 29.35 (CH2), 29.02 (CH2), 28.97 (CH2 2), 27.21 (CH2),27.17 (CH2), 25.65 (CH2), 24.59 (CH2), 22.58 (CH2), 14.08 (CH3), 13.35 (CH3). | |
With thionyl chloride In dichloromethane at 25℃; for 2h; | N-benzyloctadecanamide (2) General procedure: To a solution of hard acid (300 mg, 1.05 mmol) in DCM (10 ml) was added dichloro-sulfoxide (SOCl2, 2 ml). The reaction mixture was stirred at 25 °C for 2 h. The reaction was concentrated to dryness under reduced pressure and slowly added to a solution of benzylamine (100 mg, 0.93 mmol) in DCM (10 ml) under the catalysis of DMAP (40 mg, 0.32 mmol). The solution was stirred at 25 °C for 2 h. DCM (50 ml) and saturated aqueous NH4Cl (20 ml) was added to the reaction mixture, which was stirred for 10 mins. The organic layer was separated and dried over anhyd sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude was purified by column chromatography (silica gel petroleum-EtOAc, 50:1) to give the compound 2 as a yellow oil (280 mg, 80.5%). | |
With oxalyl dichloride In benzene at 20℃; for 4h; Inert atmosphere; | 7 [0237] To a solution of linoleic acid (2.36 g, 8.4 mmol) in anhydrous benzene (50 mL) was added dropwise oxalylchloride (1.45 g, 11.4 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 4 hours. Solventand excess of oxalyl chloride was removed in vacuo to give linoleyol chloride as light yellowish oil. | |
With oxalyl dichloride In dichloromethane at 20℃; Inert atmosphere; | 7 Synthesis of linoleoyl chloride (2g) Linoleic acid (110 mg, 0.39 mmol) was dissolved in dichloromethane (3.0 mL), after adding oxalyl chloride (100 μL, 1.16 mmol) and stirred at room temperature under a nitrogen atmosphere. Tracking of the reaction, the reaction mixture pyridine: methanol = 1: a small amount quenched with 1 solution, the methyl ester of linoleic acid was followed by confirming on TLC. After four hours, to give an oily residue and the solvent was evaporated under reduced pressure. Purification of the residue is not performed, it was used in the next reaction. | |
With oxalyl dichloride In N,N-dimethyl-formamide; benzene at 20℃; for 3h; Inert atmosphere; | COMPOUND 2: i-(tert-butyIdimethylsilyl)-2-linoleoyl-3- dimethylaminopropane-i , 2-diol : Linoleoyl chloride was prepared by adding oxalyl chloride (0.30 mL, 3.60 mmol, 1.80 equiv.) to a stirring, room temperature benzene (5 mL) solution of linoleic acid (673 mg, 2.40 mmol, 1.20 equiv. relative to alcohol) and DMF (18 L, 0.24 mmol, 0.12 equiv.) in a round bottom flask under argon. After 3 h, the volatiles were removed on a rotary evaporator and the residue azeotroped with benzene (2 5 mL), then dried under high vacuum for 3 h and used immediately without further purification. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | ||
With oxalyl dichloride In benzene at 20℃; for 6h; Inert atmosphere; | General Method for Preparing FA Acid Chlorides. General procedure: A solution of the appropriate FA (0.002 mol) in anhydrousC6H6 (15 mL) was stirred, treated with oxalyl chloride (0.19 mL, 0.0022 mol), held at room temperature under Ar for 6 h, and evaporated in a rotary evaporator. The product was again dissolved in C6H6 and evaporated to remove traces of oxalylchloride and dissolved in anhydrous CH2Cl2 (15 mL) for subsequent acylation of N-deacetyllappaconitine (1). | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; Schlenk technique; | 4.1.1. general procedure for the preparation of acid chlorides 8a-f General procedure: To a stirred solution of the fatty acid (1 eq., 0.78 mmol) and a dropof DMF in dry dichloromethane (5 ml) was added dropwise oxalylchloride (3 eq., 297 mg, 2.34 mmol) at 0 °C. The reaction mixture waswarmed slowly up to rt and stirred for further 3 h. Solvent and excessoxalyl chloride were removed in vacuo and the resulting acid chloridewas used next step without purification. | |
With thionyl chloride In dichloromethane at 40℃; | 5 Example 5. Preparation of linoleoyl chloride Reflux device (Reflux apparatus) , 200 mL of dichloromethane was added to a 40 DEG C water bath reaction vessel connected to the reactor, (Linoleic acid, 18: 2n-6) 20 mL was added, and an appropriate amount of thionyl chloride was added thereto with appropriate stirring to initiate the reaction. After a certain period of time, the reaction product was purified using a rotary evaporator Respectively. The recovered linolenic acid was used in the production of fatty acid derivatives of the other examples. | |
With oxalyl dichloride In dichloromethane at 20℃; for 2.16667h; Cooling with ice; | 5.1 Linoleic acid (5.61 g, 20 mmol), was dissolved in 50 mL DCM and cooled down in an ice bath. Oxalyl chloride (5 g, 40 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred for further 10 min in an ice bath and returned to room temperature and stirred for additional 2h. The excess oxalyl chloride was removed and the residue was redissolved in DCM and evaporated to dryness to remove the Oxalyl chloride and obtain an oily residue of linoleoyl chloride. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; for 3h; Inert atmosphere; | 1.1.3; 1.1.5; 1.1.6; 1.1.7; 1.1.8 In a round bottom flask were introduced linoleic acid (1.24 mL, 4.0 mmol) and dichloromethane (8 mL) under inert atmosphere. The mixture was cooled to 0°C and oxalyl chloride (0.38 mL, 4.4 mmol) was introduced dropwise. Then the catalytic quantity of dimethylformamide (DMF) (0.03 mL) was added. The reaction mixture was stirred for 1h at 0°C and for 2h at room temperature (20-25°C). Solvents and oxalyl chloride were removed under reduced pressure and the product was directly engaged in the following step (aspect: colorless oil with slight precipitate). | |
With oxalyl dichloride at 0 - 20℃; for 24h; Inert atmosphere; | 1 Example 1: Synthesis of Linoleoyl Chloride (1) Oxalyl chloride (47.0 mL, 555 mmol) was added to a solution of linoleic acid (70.0 g, 250 mmol) in 580 mL anhydrous methylene chloride at 0° C. under N2 atmosphere. The reaction was warmed to room temperature and stirred vigorously for 24 hours. Solvent and oxalyl chloride were removed under reduced pressure to yield linoleoyl chloride as a brown oil, which was used without further purification. | |
With oxalyl dichloride In neat (no solvent) at 15 - 20℃; for 3h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 8 Example 8 Preparation of (2,4-dinitrophenoxy) linoleic acid methyl ester (8) Prepare a 250mL three-necked flask with magnetic stirring, N2 inlet and dropping funnel. Add the compound linoleic acid (15.0g, 53.5mmol, 1.0eq), dichloromethane (150ml), DMF (2drop) to the reaction flask, and replace with nitrogen. Under stirring at room temperature, oxalyl chloride (8.15 g, 64.2 mmol, 1.5 eq) was added dropwise. Continue to stir after dripping. When no gas is generated, stir for another 1 hour. The reaction solution was distilled under reduced pressure to remove dichloromethane and residual oxalyl chloride. 17.6 g of linoleic acid chloride was obtained (yield over 100%), and the obtained compound was directly put into the next step without purification. | |
With thionyl chloride In N,N-dimethyl-formamide; benzene at 90℃; for 1.16667h; | 2.7.1. Synthesis of Z-octadeca-9,12-dienoyl chloride 1 In a single-neck round bottomflask, 5ml of DMF in dry benzene anda solution of 12-octadecadienoic acid (0.5 g, 0.0015 mol) were placed.The flask was equipped with a condenser. A dropping funnel was usedto slowly add SOCl2 to the mixture as the reaction is endothermic. Themixture was stirred for 10 min and heated in oil for 1 h at 90 °C. Ittook 10 min on a rotary to remove all solvent from the mixture. Thecis-9, cis-12-octadecadienoyl chloride thus made was used for additionalreaction as shown in the second part.1H NMR: (δ, ppm): 0.86 (t, 3H, -CH3), 1.28-1.30 (m, 14H, -CH2-),1.92 (m,2H, -CH2-CH2-C=O), 2.02 (q, 4H, -CH2-CH=), 2.73 (t, 2H, =CH-CH2-CH=), 2.84 (t, 2H, -CH2-CO-Cl), 5.32 (t, 4H, -CH=CH-); 13CNMR: (δ, ppm): 14.1 (1C, -CH3), 23.2 (1C, -CH2-CH3), 24.3 (1C, -CH2-),25.0 (1C, -CH2-CH2-CO-), 27.2 (2C, -CH2-CH=CH-), 28.9-32.6 (6C,-CH2-), 47.1 (1C, -CH2- CO-), 129.8-137.2 (4C, -CH=CH-), 172.6 (1C,-C=O). Exact mass: m/e 298.21 (100.0%), 300.20 (32.0%), 299.21(20.5%), 301.21 (6.6%), 300.21 (2.1%). Anal. calcd. for C18H31ClO(298.89); C, 72.33; H, 10.45; Cl, 11.86; found: C, 72.43; H, 10.25; Cl,11.90. | |
With oxalyl dichloride In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; | 1 Example 1 : Synthesis of linoleoyl chloride (1 ) Oxalyl chloride (47.0 mL, 555 mmol) was added to a solution of linoleic acid (70.0 g, 250 mmol) in 580 mL anhydrous methylene chloride at 0 °C under l atmosphere. The reaction was warmed to room temperature and stirred vigorously for 24 hours. Solvent and oxalyl chloride were removed under reduced pressure to yield linoleoyl chloride as a brown oil, which was used without further purification | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; | 26 [Example 26] Synthesis of Glycerol Derivative (EC-A05) Linoleic acid (588.9 mg, 2.1 mmole, 1 eq.) was added to 10 ml of anhydrous MC. Oxalyl chloride (Cl-CO-CO-Cl, 2eq.) was dissolved in 1.1 ml of MC, and added to the reaction mixture, and stirred. A solution of 20 ml of MC and DMF (0.1 eq.) was added to the reaction mixture and stirred at 20° C. for 1 hour. The reaction was confirmed by TLC (PE:EA=5:1, Rf=0.3). When the reaction was complete, 627.67 mg of linoleic chloride, a crude product obtained by concentrating the reaction product, was directly used in the next step. Linoleic chloride synthesized above was added to 5 ml of THF at 0-10° C. and stirred. While maintaining 0-10° C., a solution of the starting material, 2-mercapto-1,3-propanediol (454.27 mg, 4.2 mmole, 2eq.) and TEA (2eq.) were added to 15 ml of THF, and added it to the above mixture. And then it was stirred at the same temperature for 1 hour. The reaction was confirmed by TLC (MC:MeOH=20:1, Rf=0.2). When the reaction was complete, the reaction solution was diluted with 20 ml of Hex (hexane), filtered, and concentrated. After dissolving in 10 ml of chloroform, it was washed with purified water. And then, the organic layer was dehydrated with sodium sulfate (Na2SO4), filtered, and concentrated. It was purified by column (PE:EA=1:1) to obtain the target compound 27(L=linoleoyl, yield=59.05%). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | Synthesis of ps314b Oxalyl chloride (0.72 mL, 8.36 mmol) wasadded over 10 min to a solution of linoleic acid (2 mL, 6.43 mmol) andDMF (3 drops) in DCM (10 mL) at 0 C, and the solution stirred at roomtemperature overnight. The solvent and excess oxalyl chloride wasremoved in vacuo and the residue redissolved in DCM (10 mL). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | 14 Synthesis of 3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-1H-indol-4-yl (9Z,12Z)-octadeca- 9,12-dienoate (I-48) A solution of linoleic acid (0.22 g, 0.77 mmol) in dry CH2CI2 (10 mL) was treated with oxalyl chloride (0.09 mL, 1.02 mmol), followed by dry DMF (1 drop) at room temperature and stirred for additional 2 h. Solvent was evaporated and dried on high vacuum to obtain the crude acid chloride. A solution of (R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)- 1 H-indol-4-ol (0.12 g, 0.51 mmol) in dry CH2CI2 (10 mL) and triethylamine (0.21 mL, 1.54 mmol) was treated with above crude acid chloride in dry CH2CI2 (10 mL) at 0 °C. The reaction was brought to room temperature and stirred for additional 2 h. The reaction was quenched with water (50 mL) and product was extracted into CH2CI2 (2 x 50 mL). Combined CH2CI2 layer was washed with brine (25 mL) and dried (Na2S0 ). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH: CH2CI2, 5:95) on silica gel to obtain the title compound I-48 (0.21 g, 84%) as pale-yellow oil. 1H NMR of TFA salt (DMSO- cfe): 5 11.29 (s, 1 H), 9.61 (brs, 1H), 7.30-7.28 (m, 2H), 7.09 (t, 1H, J = 6.0 Hz), 6.73 (d, 1H, J = 6.0 Hz), 5.41-5.32 (m, 4H), 3.66-3.57 (m, 2H), 3.29-3.10 (m, 2H), 2.93-2.88 (m, 1H), 2.78-2.69 (m, 4H), 2.10-1.66 (m, 12H), 1.37-1.25 (m, 12H), 0.87 (t, 3H, J = 6.0 Hz); ESI-MS (m/z, %): 496 (MH+, 100). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; | 4 Synthesis of (9Z,12Z)-Octadeca-9,12-dienoyl chloride (2) To a solution of Linolenic acid (1.0 g, 3.6 mmol) in 10 mL dichloromethane at 0 °C, was addedN, V-di methyl formamidc (0.1 mL) and oxalyl chloride (1.2 mL, 14.3 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. The solvent was removed to the under reduced pressure, and the crude was used in next step without further purification. | |
With oxalyl dichloride In dichloromethane at 2 - 5℃; for 3h; | 3.2.2. General procedure for Acyl Chlorides Synthesis General procedure: To a magnetically stirred at 2-5 C solution of carboxylic acid (8.92 mmol) indichloromethane (10 mL), oxalyl chloride (17.80 mmol) was added and the solution wasstirred for 3 h. The evaporation of the solvent and excess of oxalyl chloride gave quantitativelyacyl chloride, which was used without further purification | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; | Synthesis of (9Z,12Z)-Octadeca-9,12-dienoyl chloride (2) To a solution of Linolenic acid (1.0 g, 3.6 mmol) in 10 mL dichloromethane at 0 °C, was added N, N-dimethylformamide (0.1 mL) and oxalyl chloride (1.2 mL, 14.3 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. The solvent was removed to the under reduced pressure, and the crude was used in next step without further purification. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; | Synthesis of (9Z,12Z)-Octadeca-9,12-dienoyl chloride (2) To a solution of Linolenic acid (1.0 g, 3.6 mmol) in 10 mL dichloromethane at 0 °C, was added N, N-dimethylformamide (0.1 mL) and oxalyl chloride (1.2 mL, 14.3 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. The solvent was removed to the under reduced pressure, and the crude was used in next step without further purification. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; | 5.1 Synthesis of (9Z,12Z)-Octadeca-9,12-dienoyl chloride (2) To a solution of Linolenic acid (1.0 g, 3.6 mmol) in 10 mL dichloromethane at 0 °C, was added N, 7V-dimethylformamide (0.1 mL) and oxalyl chloride (1.2 mL, 14.3 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. The solvent was removed to the under reduced pressure, and the crude was used in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With lithium aluminium tetrahydride; In tetrahydrofuran;Reflux; | Lithium aluminum hydride (2.73 g, 72 mmol) was suspended in tetrahydrofuran (THF, 190 mL) cooled at 4 C. Linoleic acid (10 g, 36 mmol) was added dropwise to the suspension, and the resulting mixture was stirred for 10 minutes. Then, the mixture was refluxed overnight with heating on an oil bath. After cooling the mixture, 1 mol/L aqueous sodium hydroxide (100 mL) was added to terminate the reaction. Then, the reaction mixture was diluted with ethyl acetate (100 mL), and filtered, and the filtrate was washed with saturated aqueous sodium hydrogencarbonate. Then, the organic layer was collected, and dried over anhydrous sodium sulfate. The organic layer was filtered, and the solvent was evaporated by using a rotating evaporator to obtain a crude product. The crude product was purified by silica gel chromatography (elution solvent, hexane:ethyl acetate, continuous gradient) to obtain 9z,12z-octadecadien-1-ol (8.68 g, 32.6 mmol) as colorless oil. Yield was 91%. Proton nuclear magnetic resonance (1H NMR, 500 MHz) data of 9z,12z-octadecadien-1-ol delta=0.88 (t, 3H), 1.25-1.36 (m, 16H), 1.53-1.58 (m, 2H), 2.02-2.06 (m, 4H), 2.76 (t, 2H), 3.62 (t, 2H), 5.29-5.40 (m, 4H) |
91% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 25℃; | In a round bottom flask was suspended LiAlH4 (0.18 g, 4.8 mmol) in THF (25 mL). A solution of linoleic acid (1.24 mL, 4.0 mmol) in THF (15 mL) was added dropwise at 0C. The mixture was slowly warmed up to room temperature (20-25C) and stirred overnight. The mixture was quenched by addition of distilled water (2 mL) and 15 % aqueous NaOH (5 mL). The mixture was diluted in EtOAc, transferred in a separating funnel then washed with brine. The organic phase was dried over MgSO4 and concentrated. The product was purified by a column chromatography on SiO2 (petroleum ether/ ethyl acetate (5:1), Rf = 0.80). mpure = 0.96 g. Aspect: colorless oil. Yield: 91%. 1H NMR (500 MHz, CDCl3) delta (ppm): 5.42-5.33 (m, 4H), 3.66 (t, 2H, J = 6.6 Hz), 2.80 (m, 2H), 2.07 (m, 4H), 1.59 (m, 2H), 1.39-1.31 (m, 16H), 1.26 (broad s, 1H), 0.91 (t, 3H, J = 7.0 Hz). 13C {1H} NMR (126 MHz, CDCl3) delta (ppm): 130.20, 130.10, 128.01, 127.93, 63.07, 32.81, 31.52, 29.64, 29.48, 29.39, 29.34, 29.22, 27.20, 25.73, 25.63, 22.55, 14.03. One C is missing HRMS calcd for C18H34ONa [M+Na]+ 289.2501, found 289.2503. |
85% | With lithium aluminium tetrahydride; In diethyl ether; for 3.0h;Reflux; | First, linoleic acid was converted to linoleoyl. 4.5 mmol LiAIH4 (0.17 g - 1.25 equivalent of acid to reduce) wassuspended in 20 ml dry diethyl ether. 1g (3.57 mmol) of linoleic acid was added dropwise in 10 ml diethyl ether, and itwas ensured that the addition created a gentle reflux. The reaction vessel was protected from light to prevent degradation.The reaction was continually stirred for 3 hours and left overnight to ensure completion as determined by TLC. The flaskwas placed in an ice water bath and 4 ml of 10 % sulphuric acid was added with care. The organic layer was decanted,and aqueous suspension washed with ether (20 ml x3). The ether fractions were combined and washed with water twiceand dried over Na2SO4, filtered and evaporated to obtain a white-yellowish wax, linoleoyl (85 % yield). |
28.2 g | With sodium bis(2-methoxyethoxy)aluminium dihydride; In tetrahydrofuran; toluene; at 0 - 20℃;Inert atmosphere; | A 1 L glass reactor fitted with an argon inlet was purged with dry argon, and charged with of linoleic acid (30 g, 107 mmol) and THF (320 mL). The reaction mixture was cooled to 0 C. with acetone-dry-ice mixture. While maintaining the reaction temperature below 0 C., 73 mL of sodium his (2-methoxyethoxy) aluminum hydride solution in methylbenzene (60% wt/vol) was added drop wise. After the completion of addition, the reaction mixture was incubated at ambient temperature for 2 hours. After reaction, the reaction mixture was cooled to 0 C. To the reaction mixture, a saturated sodium sulfate solution (prepared by dissolving 5.75 g Na2SO4 in 7.85 mL of water) was added drop wise over a period of more than 45 minutes; then, 130 mL of ethyl acetate was added drop wise to the reaction over a period of 30 minutes, with violent stir. The reaction mixture was filtered and the residues were washed with ethyl acetate. The organic layers were combined and concentrated. The resulting product was dissolved in 90 mL of ethyl acetate and washed twice with 45 mL of water, and dried over anhydrous sodium sulfate. Then, the solution was filtered, the organic layer was concentrated to remove the organic solvent with a vacuum pump, resulted in 28.8 g of product 2. |
With vitride; In tetrahydrofuran; toluene; at 0 - 20℃; for 5.75h;Inert atmosphere; Large scale; | A clean, dry 200 L glass reactor fitted with an argon inlet and thermowell was charged with 60 L of THF and 5.73 Kg (20.4 mol) of linoleic acid. The contents of the reactor were cooled below 00 C. using an acetone-dry ice bath. To this cold solution 13.8 L of Vitride (60% wt/vol) in toluene was added slowly maintaining the internal temperature of the reaction mixture below 00 C. (Note: Initial addition of vitride was exothermic and frothing was observed. The frothing ceased afier 15 minutes of addition). The addition of vitride took 3and 45 minutes. Afier completion of the addition, the reaction mixture was stirred at ambient temperature for 2 hr. An aliquot was taken and quenched with sat. Na2SO4 and the thus obtained crude product was analyzed by TLC for the presence of the starting acid. The TLC showed completion of the reaction and the reaction mixture was again cooled belowC. in about 45 minutes.A saturated solution of sodium sulfate (prepared by dissolving 1.1 Kg of sodium sulfate in 1.5 Lwater) was slowly added to the reaction mixture over 45 mm. After completion of the addition, 25 L of ethyl acetate was added over a period of 30 mm with stirring. The obtained reaction mixture was filtered through a celite bed overperiod of 45 mm and the celite bed was washed withadditional 17 L of ethyl acetate to remove all product from the residue. The combined organics were concentrated under reduced pressure. The residue was dissolved in 15 L of ethyl acetate and the organic layer was washed with water (2x7and dried over sodium sulfate (1.1 Kg). After filtration the organic layer was concentrated under reduced pressure and dried under high vacuum to obtain the product linoleyl alcohol as an oil. Crude yield=5.5 Kg (theoretical yield=5 .43 Kg). This product was used without thrther purification in the next step. | |
In tetrahydrofuran; toluene; at 0 - 20℃; for 2.0h;Inert atmosphere; | A clean dry 200 L glass reactor fitted with an argon inlet and a thermowell was charged with 60 L of THF and 5.73 Kg (20.4 mol) of linoleic acid. The contents of the reactor were cooled to below 0 C. using an acetone-dry ice bath. To this cold solution, 13.8 L of VITOLIDE (60% w / v) in toluene was slowly added and the internal temperature of the reaction mixture was kept below 0 C (note: the addition of the initial VITOLID was exothermic Yes, foaming was observed, foaming stopped 15 minutes after addition). It took 3 hours and 45 minutes to add Vitride. After the addition was complete, the reaction mixture was stirred at ambient temperature for 2 hours. An aliquot was taken and quenched with saturated Na2SO4 and the crude product so obtained was analyzed by TLC for the presence of the starting acid. TLC indicated the completion of the reaction and the reaction mixture was again cooled below 0 C. in about 45 minutes. To this mixture was slowly added a saturated sodium sulfate solution (prepared by dissolving 1.1 Kg of sodium sulfate in 1.5 L of water) over 45 minutes. After the addition was completed, 25 L of ethyl acetate was added with stirring over 30 minutesWas added. The resulting reaction mixture was filtered through a pad of celite over 45 minutes and the celite bed was washed with an additional 17 L of ethyl acetate to remove all the product from the residue. The combined organics were concentrated under reduced pressure. The residue was dissolved in 15 L of ethyl acetate and the organic layer was washed with water (2 × 7 L) and dried over sodium sulfate (1.1 Kg). After filtration, the organic layer was concentrated under reduced pressure and dried under high vacuum to give the product linoleyl alcohol as an oil. Crude yield = 5.5 Kg (theoretical yield = 5.43 Kg). This product was used in the next step without further purification. | |
28.8 g | With sodium bis(2-methoxyethoxy)aluminium dihydride; In toluene; at 0 - 20℃; for 2.0h; | 30 g of linoleic acid (Reactant 1) and THF (320 ml) were added to the reactor. 73 ml of a red aluminum solution (60% wt/vol) in toluene was slowly added dropwise to the reactor, keeping the temperature at about 0C during the addition. After the addition was completed, the reaction was performed at room temperature for 2 hours.The solution was cooled to 0C and saturated sodium sulfate solution was slowly added.After the addition was completed, 130 ml of ethyl acetate was added dropwise over 30 minutes.Stir vigorously. The reaction solution was filtered and the solid was washed with ethyl acetate. The organic phases were combined and concentrated. The product was dissolved in 80 ml of ethyl acetate, washed twice with water, and dried over anhydrous sodium sulfate. filter,The organic phase was concentrated to remove the solvent to give product 2 (28.8 g). |
28.8 g | With sodium bis(2-methoxyethoxy)aluminium dihydride; In tetrahydrofuran; at 0 - 20℃; for 2.0h; | 30 g of linoleic acid (Reaction 1) and THF (320 ml) were charged to the reactor. 73 ml of a Sodium bis(2-methoxyethoxy)aluminium hydride (trade name Red-Al) solution (60% wt/vol) in toluene solution was slowly added dropwise to the reactor, and the temperature was maintained at about 0 C during the dropwise addition. After the completion of the dropwise addition, the reaction was carried out for 2 hours at room temperature. The solution was cooled to 0 C and a saturated sodium sulfate solution was slowly added. After the dropwise addition was completed, 130 ml of ethyl acetate was added dropwise within 30 minutes, and vigorously stirred. The reaction mixture was filtered, solid was washed with ethyl acetate, and then organic phases were combined and concentrated. The product was dissolved in 80 ml of ethyl acetate, washed twice with water and dried over anhydrous sodium sulfate. Filtration and concentration was carried out for the organic phase to remove solvent, and obtain Intermediate 2 (28.8 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dichloro(dimethylglyoxime)(dimethylglyoximato)cobalt(III); 9-mesitylacridine In dichloromethane; acetonitrile at 25 - 27℃; for 36h; Irradiation; | |
47% | With pyridine; lead(IV) acetate; copper diacetate In benzene for 2h; Heating; | |
34% | With pyridine; copper diacetate; lead(IV) tetraacetate In benzene at 80℃; for 2h; |
With lead(IV) acetate; copper diacetate In pyridine; benzene |
Yield | Reaction Conditions | Operation in experiment |
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100% | With dmap In dichloromethane at 20℃; | |
89% | With dmap; dicyclohexyl-carbodiimide | |
With dmap; dicyclohexyl-carbodiimide In diethyl ether at 20 - 25℃; for 4.5h; |
With dmap; dicyclohexyl-carbodiimide at 20℃; | ||
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; | 4.2.2. Acylation of 2 with acid and DCC A solution of DCC (824 mg, 4 mmol) in dry CH2Cl2 (7 mL) was added dropwise to a stirred and ice-cooled solution of (9Z,12Z)-n-C5H11CHCHCH2CHCH(CH2)7CO2H (linoleic acid, 560 mg, 2 mmol), (+/-)-2 (264 mg, 2 mmol), and DMAP (15 mg, 0.12 mmol) in dry CH2Cl2 (10 mL) over 30 min at 0-5 °C. Stirring was continued for 1 h at 0-5 °C, and the mixture was left to stand overnight at room temperature. It was then diluted with hexane and filtered through Celite. The Celite layer was washed with hexane. The combined filtrate and washings were concentrated in vacuo. The residue was chromatographed over SiO2 (15 g). Elution with hexane/EtOAc (20:1) gave 836.5 mg (quant.) of (+/-)-3e contaminated with DCC, which could be removed in the next step. Preparation of 3b and 3e was executed by the above procedure. | |
97.08 %Chromat. | With tetra-n-butylammonium tetrafluorborate In toluene at 120℃; for 3h; | 2.4.5. Synthesis of fatty acid solketal esters General procedure: All the reactions involved 200mL of toluene, 0.1321g of SiO2-SO3H, 0.1321g of (Bu4N)(BF4), and 1.3216g solketal (10mmol). The amount of catalyst on each run was adjusted to maintain a constant 20%- 10% SiO2-SO3H and 10% (Bu4N)(BF4) mass-to-mass ratio to the solketal. 40.0mmol of each of the fatty acids were used: 5.7685g of caprylic acid, 8.01271g lauric acid, 11.3792g stearic acid, 11.2179g linoleic acid and 11.2988g of oleic acid, respectively. The reactions were heated for 2 or 3-h depending of the fatty acid (Table 1 ) using a 500mL two-necked round bottom flask equipped with a reflux condenser. The final temperature of the slurries did not exceed 120°C. The vessels were cooled to room temperature, the mixtures were filtered and toluene was eliminated by distillation. The organic extracts were diluted with 20mL diethyl ether and filtered in silica to retired the (Bu4N)(BF4). The ethereal phase was washed with 100.0mL of a saturated, aqueous solution of NaHCO3, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified on a chromatographic column using hexane and ethyl acetate as eluents to obtain the pure FASEs as colorless oils very good yield (CG/MS, Table 1). The catalysts were recovered as before. The FASEs were identified by GC/MS, ESI-TOF MS and 1H and 13C NMR spectroscopy. (Voir Scheme 1 .) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; | 2 2.1.1. Fatty acid coupling to 3-aminopyridine General procedure: In a typical synthesis procedure to a solution of 7.08mmol of fatty acid in 50mL of DCM, 8.496mmol of 3-aminopyridine (1.2 equivalents) and 8.496mmol of EDC-HCl (1.2 equivalents) were added and stirred for 12h at room temperature. The reaction mixture was diluted to 100mL with DCM and washed with 50mL water and 1M HCl solution to remove EDC urea, excess EDC-HCl and 3-aminopyridine. Thereafter, DCM fraction was washed with 1M sodium carbonate solution to neutralise any HCl associated with pyridine structure of the product formed. |
With dicyclohexyl-carbodiimide In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 1 Intermediate lb: 2-oxopropane-l,3-diyl (9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12- dienoate) To a solution of dihydroxyacetone (1.55 g, 1.0 equiv) in DCM (0.1 M) was added linoleic acid (2.05 equiv), DMAP (0.2 equiv), DIPEA (2.4 equiv), and EDCI (2.4 equiv). The reaction was stirred at room temperature for at least 18 h. Upon completion, the mixture was quenched by the addition of water, and the organic layer was washed lx with 1 M HC1 and lx with 5% NaHCCb. The organic layer was then dried over NaiSCri, filtered, and concentrated in vacuo. Crude material was purified by column chromatography (EtO Ac/hexanes) to product as a colorless oil (8.0 g, 75%). 'H NMR (400 MHz, CDCb) d 5.44 - 5.28 (m, 8H), 4.75 (s, 4H), 2.82 - 2.74 (m, 4H), 2.42 (t, J = 7.5 Hz, 4H), 2.05 (q, J = 6.7 Hz, 8H), 1.67 (q, J = 7.4 Hz, 4H), 1.40 - 1.24 (m, 28H), 0.95 - 0.86 (m, 6H). |
40% | With hydrogenchloride; dmap; dicyclohexyl-carbodiimide for 48h; Ambient temperature; | |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane | 21.A To a solution of (9Z,12Z)-octadeca-9,12-dienoic acid (1.107 rnL) in dichloromethane (20 rnL) were added 1 ,3-dihydroxypropan-2-one (0.161 g), DMAP (0.436 g), and EDCI -HCl (0.718 g). The mixture was stirred overnight, quenched with water and extracted with dichloromethane. The extract was washed with water and brine, dried over Na2SO4, filtered and concentrated. The concentrate was purified by flash chromatography (Analogix SF25x40g with 10:lhexanes/ethyl acetate). MS (ESI) m/z 612A (M+18)+. |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In ethanol at 20℃; for 0.333333h; tomato homgenate; Yield given; | ||
With oxygen | ||
With oxygen at 25℃; for 0.75h; potato lipoxygenase, sodium acetate buffer, sodium borat buffer, aq. NaOH, Tween 20; Yield given; |
With oxygen at 5℃; barley seed lipoxygenase; | ||
With phosphate buffer; tomato lipoxygenase; Tween 20 for 5h; | ||
With recombinant barley LOX-1 | ||
With sodium acetate buffer In ethanol at 20℃; for 0.0833333h; | ||
With tomato fruit lipoxygenase; oxygen at 0℃; | ||
With St-lipoxygenase1 In aq. phosphate buffer Enzymatic reaction; regioselective reaction; | ||
With recombinant maize 9-lipoxygenase; oxygen In aq. phosphate buffer at 0℃; Enzymatic reaction; | ||
With recombinant lipoxygenase ZmLOX3 from Zea mays; oxygen In aq. phosphate buffer at 0℃; Enzymatic reaction; | ||
With recombinant maize 9-lipoxygenase; oxygen In aq. phosphate buffer at 0℃; Enzymatic reaction; | ||
With recombinant maize 9-lipoxygenase; oxygen In aq. phosphate buffer at 0℃; Enzymatic reaction; | 4.1. Chemicals and materials Linoleic and α-linolenic acids, as well as the soybean lipoxygenase type V, were purchased from Sigma. NaBH4 and silylating reagents were purchased from Fluka (Buchs, Switzerland). (9S,10E,12Z)-9-Hydroperoxy-10,12-octadecadienoic acid (9-HPOD) and (9S,10E,12Z,15Z)-9-hydroperoxy-10,12,15-octadecatrienoic acid (9-HPOT) were prepared by incubation of linoleic and α-linolenic acids, respectively, with the recombinant maize 9-lipoxygenase (GeneBank: AAG61118.1) (Wilsonet al., 2001) in Na-phosphate buffer (100 mM, pH 6.0) at 0 °C, under continuous oxygen bubbling. (9Z,11E,13S)-13-Hydroperoxy-9,11-octadecadienoic acid (13-HPOD) and (9Z,11E,13S,15Z)-13-hydroperoxy-9,11,15-octadecatrienoic acid (13-HPOT) were obtained by incubation of linoleic and α-linolenic acids, respectively, with the soybean lipoxygenase type V in Tris-HCl buffer (50 mM, pH 9.0) at 23 °C, under continuous oxygen bubbling. The extracted hydroperoxides (as free carboxylic acids) were purified by normal phase HPLC (NP-HPLC) on Macherey-Nagel Nucleodur 100-3 silica column (250 × 4.6 mm, 3 μm) under the isocratic elution with the solvent mixture hexane/isopropanol/acetic acid (98.1:1.8:0.1, by volume) at a flow rate of 0.4 ml/min. Hydroperoxides were chromatographically pure and at least 98% optically pure, as judged by chiral phase HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With thionyl chloride at 0 - 20℃; | 1.2 4.1.1.2. Methyl (9Z,12Z)-octadeca-9,12-dienoate (3) Thionyl chloride (0.5 ml, 6.239 mmol) was added dropwise to commercially available linoleic acid 1 (700 mg, 2.495 mmol) dissolved in MeOH at 0 °C. The reaction was stirred at room temperature and monitored by TLC. Upon completion, H2O was added and the reaction mixture was concentrated in vacuo. The resulting solution was extracted with ethyl acetate, dried over MgSO4, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (n-hexane/EtOAc, 10:1) and 3 (712 mg, 96%) was obtained as a brown oil. |
90% | With polysiloxane acidic ionic liquids containing pyridinium trifluoroacetate salts for 4h; Reflux; | 2.6 General procedure for biodiesel production using PMO-Py-IL materials General procedure: In a typical reaction, fatty acids (10 mmol), methanol or ethanol (5 mL), and PMO-Py-IL (0.1 g) as nanocatalyst were mixed in a 50 mL single-necked round bottomed flask and stirred under reflux conditions for 4 h. Upon reaction completion, the mixture was cooled down at RT, PMO-Py-IL was recovered and washed with ethyl acetate for the next run. The combined filtrate and ethyl acetate washings were washed with water and the organic layer was separated and dried over sodium sulfate, filtered, and concentrated under vacuum to provide the desired methyl esters as pure products. |
87% | With polystyryl diphenyl phosphine-iodine In dichloromethane at 40 - 50℃; for 0.833333h; |
80 - 98 %Chromat. | at 270 - 400℃; for 0.0333333 - 0.333333h; | 3.10; 3.11; 3.12; 3.4; 5.2 (Esterification Reaction of Fatty Acid) An esterification reaction of a fatty acid and methanol was conducted using, as a raw material, palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid (all manufactured by Nacalai Tesque) commercially available as a reagent, and under conditions of volume ratio, temperature, pressure and reaction time shown in Table 5. For the esterification reaction of a fatty acid and methanol, a fatty acid and methanol were filled at a mole ratio of 1:42 in a Inconel-625 reaction tube having a content volume of 5 ml, and the same procedure as in the methyl-esterification reaction in Example 1 was conducted. After removal of unreacted methanol and produced water in the same manner as in Example 1, the reaction product was dissolved in fresh methanol and HPLC analysis was conducted. From the HPLC analysis result, the conversion from a fatty acid into a fatty acid alkyl ester (=yield of methyl ester) was obtained. The results are shown in Table 5 together with reaction conditions. TABLE 5 Reac- Tem- tion Fatty Fatty acid (ml)/ perature Pressure time Yield Example acid methanol (ml) (° C.) (Mpa) (min) (%) Example 3-1C16-0 0.91:4.09 270 17 20 90 Example 3-2C16-0 0.91:4.09 300 24 7 88 Example 3-3C16-0 0.91:4.09 350 43 4 75 ComparativeC16-0 0.91:4.09 400 75 2 92 example 3-1 Example 3-4C18-0 0.91:4.09 270 17 20 98 Example 3-5C18-0 0.91:4.09 300 24 7 98 Example 3-6C18-0 0.91:4.09 350 43 4 100 ComparativeC18-0 0.91:4.09 400 75 2 100 example 3-2 Example 3-7C18-1 0.91:4.09 270 17 20 98 Example 3-8C18-1 0.91:4.09 300 24 7 98 Example 3-9C18-1 0.91:4.09 350 43 4 98 ComparativeC18-1 0.91:4.09 400 75 2 94 example 3-3 Example 3-10C18-2 0.91:4.09 270 17 20 98 Example 3-11C18-2 0.91:4.09 300 24 7 98 Example 3-12C18-2 0.91:4.09 350 43 4 87 ComparativeC18-2 0.91:4.09 400 75 2 80 example 3-4 Example 3-13C18-3 0.91:4.09 270 17 20 99 Example 3-14C18-3 0.91:4.09 300 24 7 96 Example 3-15C18-3 0.91:4.09 350 43 4 93 ComparativeC18-3 0.91:4.09 400 75 2 61 example 3-5 C16-0: palmitic acid, C18-0: stearic acid, C18-1: oleic acid, C18-2: linoleic acid, C18-3: linolenic acid An esterification reaction of a fatty acid and alcohol or a transesterification of rapeseed oil and alcohol was conducted using, as a raw material, fats and oils and alcohols shown in Table 7, under conditions of mole ratio, temperature, pressure and reaction time shown in Table 7. Since about 98.5% of rapeseed oil is composed of a tri-glyceride, the reaction from rapeseed oil can be judged to be a transesterification. The reaction product was subjected to HPLC analysis in the same manner as in Example 1, from the HPLC analysis result, conversion into a fatty acid alkyl ester from a fatty acid or rapeseed oil (=yield of alkyl ester) was obtained. The results are shown in Table 7 together with the reaction conditions. TABLE 7 Alcohol/fats and oils Temperature Pressure Reaction Example (mole ratio) Fats and oils Alcohol (° C.) (Mpa) time (min) Yield (%) Example 42/1C18-3 Methanol 300 20 8 96.2 5-1 Example 42/1C18-2 300 20 8 95.1 5-2 Example 42/1C18-1 300 20 8 95.8 5-3 Example 42/1C18-0 300 20 8 94.7 5-4 Example 42/1C16-0 300 20 8 94.0 5-5 Example 42/1 Rapeseed 300 20 15 98.0 5-6 oil Example 42/1 Rapeseed 350 43 4 98.0 5-7 oil Example 42/1C18-3 Ethanol 300 15 12 94.6 5-8 Example 42/1C18-2 300 15 14 97.4 5-9 Example 42/1C18-1 300 15 14 95.9 5-10 Example 42/1C18-0 300 15 15 91.2 5-11 Example 42/1C16-0 300 15 14 91.7 5-12 Example 42/1 Rapeseed 300 15 45 96.7 5-13 oil Example 42/1 Rapeseed 350 25 10 97.1 5-14 oil Example 42/1C18-3 1-propanol 300 10 15 97.0 5-15 Example 42/1C18-2 300 10 14 92.7 5-16 Example 42/1C18-1 300 10 14 92.3 5-17 Example 42/1C18-0 300 10 14 89.6 5-18 Example 42/1C16-0 300 10 14 90.1 5-19 Example 42/1 Rapeseed 300 10 45 96.1 5-20 oil Example 42/1 Rapeseed 350 23 14 98.8 5-21 oil Example 42/1C18-3 1-butonal 300 9 15 97.3 5-22 Example 42/1C18-2 300 9 14 92.4 5-23 Example 42/1C18-1 300 9 14 86.1 5-24 Example 42/1C18-0 300 9 14 82.5 5-25 Example 42/1C16-0 300 9 14 81.1 5-26 Example 42/1 Rapeseed 300 9 45 87.1 5-27 oil Example 42/1 Rapeseed 350 23 14 95.3 5-28 oil Example 42/1 Rapeseed 1-octanol 300 6 45 68.7 5-29 oil Example 42/1 Rapeseed 350 19 20 90.7 5-30 oil C16-0: palmitic acid, C18-0: stearic acid, C18-1: oleic acid, C18-2: linoleic acid, C18-3: linolenic acid |
With sulfuric acid at 90℃; for 2h; | ||
97 %Chromat. | With phosphotungstic acid at 25℃; for 4h; | |
98 %Chromat. | With bismuth(lll) trifluoromethanesulfonate at 150℃; for 0.0166667h; Microwave irradiation; | |
With boron trifluoride at 90℃; for 0.166667h; | ||
With 3-(N,N-dimethyldodecylammonium)propanesulfonic acid p-toluenesulfonate at 60℃; for 3h; | ||
With hydrogenchloride In chloroform at 90℃; for 1h; | ||
With boron trifluoride at 20℃; for 0.25h; | 1 2.2 Sample preparation General procedure: The procedure to convert fatty acids (FA) to fatty acid methyl esters (FAME) was described previously and is summarized in Eq. (1) [20]. Briefly, the FA (∼1mg) was treated with BF3 in a 10% methanol solution at room temperature (RT) and then extracted into a non-polar solvent (e.g., n-pentane). Fresh samples were prepared for mass spectrometry by collecting the upper n-pentane layer (∼3mM) and diluting in methanol to yield of final solution of 10-20μM in the resulting FAME. Then, each iodine-containing reagent was added to a sample of this solution to a final concentration of 5-10μM before adding 0.05% formic acid to aid the formation of protonated 4-iodoaniline (pIA) for charge adducting.Deuterium-exchanged experiments were undertaken as summarized in Eq. (2), whereby a mixture of D1-methanol and D2O (2:1) was used to dilute 1μL of the n-pentane layer to exchange all three protons in protonated amine group (-ND3+).Preparation of the D3-labeled FAME 1,1,1-trideuteromethyl (Z)-octadec-9-enoate is summarized in Eq. (3). In this procedure, 9Z-ocatadecanoic acid (1mg, 4μmol) placed in D3-methanol (CD3OH, 100μL), with the addition of sulfuric acid (2%), was heated at 70°C for 15min in an oil bath and then allowed to cool for 15min. Milli-Q water (1mL) and n-pentane (1mL) were added to the solution. After vigorous shaking, to ensure thorough mixing, the mixture was left for 30min at 4°C to allow the separation of the aqueous and organic layers. The n-pentane layer was collected with a Pasteur pipette and was prepared for mass spectrometric analysis as described above. Methyl (Z)-2,2-dideutero-octadec-9-enoate was prepared by adapting a procedure previously used to synthesize methyl 2,2-dideuteropentanoate and is summarized in Eq. (4) [21]. D1-Methanol (CH3OD, 8.13g, 246mmol) was cooled in an ice-bath under a nitrogen atmosphere and sodium metal (75.4mg, 3.28mmol) was added. After the metal had dissolved, 3.25mL of the solution was added to methyl (Z)-octadec-9-enoate (1.00g, 3.71mmol) and the resulting mixture heated at reflux under nitrogen for 48h. The solvent was removed in vacuo to yield the product as brown oil. The sample was then prepared for mass spectrometric analysis as described above. | |
With boron trifluoride diethyl etherate In benzene at 100℃; for 1h; | ||
With [(n-C4H9)4N]6[α-PW11Al(OH)O39Zr(η5-C5H5)2]2 at 80℃; for 12h; Schlenk technique; | Esterification of FFAs with methanol A sample catalyst was placed in a 60 mL Schlenk tube in air. FFAs (linoleic acid, oleic acid, palmitic acid, myristic acid and lauric acid) and methanol (49.3 mmol) were added using a micropipette. The reaction mixture was heated in an oil bath at 60 ± 2 and 80 ± 2 °C. The reaction solution was analyzed by liquid chromatography (Shim-pack VP-ODS column, 4.6 mm× 150 mm). Values of the products were assigned by comparing the obtained results with the analysis results obtained from analyzing authentic samples under thes ame conditions. The conversion (%) and turnover number (TON) was calculated as [mol of substrate]0- [mol of substrate]t}/[mol ofsubstrate]0 × 100 and [mol of corresponding product]t/[mol of catalyst], respectively. | |
With toluene-4-sulfonic acid for 3h; Reflux; | ||
311 g | With m-phenol sulfonic acid-formaldehyde resin In neat (no solvent) at 100℃; Flow reactor; | |
With sulfuric acid In chloroform at 94℃; for 0.5h; | ||
With sulfonic acid functionalized microporous ionic polymers for 7.5h; Reflux; | 2.3. Catalytic activity and transesterification of prepared PIP-C8 catalyst General procedure: Oleic acid (99.9% purified-Mackline) esterification reactions wereperformed in a 150 ml three-necked flask equipped with a magneticstirrer and a digital thermometer in an oil bath. Reactions were performedusing oleic acid (C18:1), which is the most commonly used FFAto evaluate the catalytic performance [20], and 95 mg of catalystloading at ethanol reflux temperature with different alcohol to acidmolar ratios. The acid value of the ethyl oleate phase was determined bytitration after the removal of excess ethanol with a standard potassiumhydroxide (0.01 mol L-1) potassium hydroxide (KOH, energy chemical,99.0%) solution [21]. | |
With thionyl chloride at 0 - 50℃; for 1h; | 3.4.2. Esterification The free fatty acids were dissolved in MeOH (500 L). Each solution was cooled downto 0 C. SOCl2 (20 L, 275.4 mol) was added, and the solution was stirred for 1 h at 50 C.The solution was concentrated under reduced pressure, and H2O (500 L) was added.The aqueous solution was extracted with a mixture of Et2O/heptane, 5:95 (2 mL). Theorganic layers were filtered on a Na2SO4/SiO2 column and concentrated to afford fattyacid methyl esters. | |
With sulfuric acid at 80℃; for 1.5h; | Preparation of Fatty Acid Methyl Esters General procedure: A solution of methanolic sodium hydroxide (9:1, 5 mL) was added to an oil sample(30 mg) and the mixture was heated under reflux for 90 min. After cooling, deionized water(10 mL) was added and the mixture was shaken for a few seconds. Unsaponified fatty acidswere discarded by extraction with hexane (3 5 mL). The layer below was collected andadjusted to pH 3 (by 6 N HCl), followed by extraction with hexane (3 5 mL). The organiclayer was removed under reduced pressure. The obtained fatty acid was further mixedwith a solution of 2% H2SO4 in methanol, and the mixture was heated under reflux at 80 Cfor 90 min. After cooling to ambient temperature, water (0.5 mL) was added, followed byextraction with hexane (3 5 mL). The methyl ester was evaporated to dryness, weighedand solubilized in hexane (1 mL) before injection into the gas chromatograph. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.4% | With dicyclohexyl-carbodiimide In hexane at 20℃; for 4h; | D-1 D-1. Preparation of 1-palmitoyl-2-linoleoyl-3-acetylglycerol(PLA); [121] 232. 4g of 1-palmitoyl-3-acetyl glycerol obtained from the above process C was added into 1, 162m1 of hexane, and 183. 7g of linoleic acid and 141. 57g of dicyclo- hexylcarbodiimide (DCC) were added thereto at room temperature. 0. 76g of dimethylamino pyridine (DMAP) was added to the reaction mixture, and the reaction mixture was stirred for 4 hours at the same temperature. Then 5. 61g of H O was added thereto, and the reaction mixture was stirred for additional 1 hour and filtered. The filtrate was separated and purified with a column chromatography in which the stationary phase was silica gel Si-60 (230 to 400 mesh) and the eluent was the mixture of hexane and ethylacetate (the volume ratio of hexane and ethylacetate is 18 : 1) to obtain 345. 8g of the target material (theoretical amounts : 395. 4g, yield : 87. 4%). |
81% | Stage #1: linoleic acid With pivaloyl chloride; triethylamine In hexane at 0℃; Stage #2: 1-acetoyl-3-palmitoyl-rac-glycerol With dmap In hexane at 10℃; for 10h; | 14.0 g of linoleic acid (cis-9, cis-12) and 10.8 g of triethylamine were added to 180 ml of n-hexane, cooled to 0° C., and 7.0 g of pivaloyl chloride was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and then 18.0 g of 1-palmitoyl-3-acetyl glycerol and 1.0 g of 4-dimethylaminopyridine were added, and then stirred at room temperature for 10 hours. 180 ml of purified water was added, the layers were separated and the organic layer was dehydrated with MgSO4, concentrated in vacuo, and purified by silica gel column (eluent: n-Hx:EA=20:1, v/v) to give 24.9 g (yield: 81%) of the target compound. |
74.8% | With dmap; pivaloyl chloride; triethylamine In hexane at -5 - 10℃; for 12h; Inert atmosphere; | 3 [Example 3] Preparation of 1-palmitoyl-2-linoleoyl-3-acetylglycerol Add 7.67g of linoleic acid, 80mL of n-hexane and 3.31g of pivaloyl chloride to a 250mL three-necked round bottom flask, and cool the reaction to -5~10°C, and add 5.97g of triethylamine dropwise. After adding 10 g of 1-palmitoyl-3-acetylglycerol and 0.328 g of 4-dimethylaminopyridine to the reactant, the reactant was allowed to react for 12 hours while stirring under nitrogen. After the reaction was completed, 40 mL of purified water was added to the reactant, and the aqueous layer was subjected to layer separation to obtain a washed organic layer. Add 27 mL of methanol and 13.5 mL of 0.1N KOH mixed solution to the separated organic layer, wash twice, then wash with 40 mL of 95 vol% methanol-purified water mixed solution, and wash with 10 mL of 0.1 vol% hydrochloric acid. Then it was washed with 40 mL of 0.05% by weight aqueous sodium bicarbonate solution. To the washed organic layer, 8 g of activated carbon, 10 g of magnesium sulfate, and 10 g of clay were added, and the organic layer was stirred for 2 hours while maintaining 0 to 5°C.Then the activated carbon was filtered, and the organic layer was washed with n-hexane cooled to -10°C to obtain 8.5 g of light yellow oily 1-palmitoyl-2-linoleoyl-3-acetylglycerol (yield: 74.8%) . |
72.9% | Stage #1: linoleic acid With pivaloyl chloride; triethylamine In hexane at 20 - 25℃; for 0.5h; Stage #2: 1-acetoyl-3-palmitoyl-rac-glycerol With dmap In hexane at 25 - 35℃; for 6h; | 3 [Example 3] Preparation of rac-1-palmitoyl-2-linoleoyl-3-acetylglycerol [Example 3] Preparation of rac-1-palmitoyl-2-linoleoyl-3-acetylglycerol Linoleic acid (99%, 2.89 g) and pivaloyl chloride (1.262 ml) were added to hexane (28.9 ml), and triethylamine (2.857 ml) was slowly added thereto at the solution temperature of 20 to 25 °C. The reaction mixture was stirred for 30 minutes to produce a mixed anhydride. After adding rac-1-palmitoyl-3-acetylglycerol (3.726 g) prepared in Example 1 and 4-dimethylaminopyridine (DMAP, 61 mg) to the reaction mixture including the mixed anhydride, the reaction mixture is stirred for 6 hours at 25 to 35 °C, and a purification process such as an extraction and an adsorption is carried out to obtain rac-1-palmitoyl-2-linoleoyl-3-acetylglycerol (4.63 g, Yield: 72.9%). |
72.9% | Stage #1: linoleic acid With pivaloyl chloride; triethylamine In hexane at 20 - 25℃; for 0.5h; Stage #2: 1-acetoyl-3-palmitoyl-rac-glycerol With dmap In hexane at 25 - 35℃; for 6h; | 3 Preparation of rac-1-palmitoyl-2-linoleoyl-3-acetylglycerol Example 3 Preparation of rac-1-palmitoyl-2-linoleoyl-3-acetylglycerol Linoleic acid (99%, 2.89 g) and pivaloyl chloride (1.262 ml) were added to hexane (28.9 ml), and triethylamine (2.857 ml) was slowly added thereto at the solution temperature of 20 to 25° C. The reaction mixture was stirred for 30 minutes to produce a mixed anhydride. After adding rac-1-palmitoyl-3-acetylglycerol (3.726 g) prepared in Example 1 and 4-dimethylaminopyridine (DMAP, 61 mg) to the reaction mixture including the mixed anhydride, the reaction mixture is stirred for 6 hours at 25 to 35° C., and a purification process such as an extraction and an adsorption is carried out to obtain rac-1-palmitoyl-2-linoleoyl-3-acetylglycerol (4.63 g, Yield: 72.9%). |
47.8% | With dmap; pivaloyl chloride; triethylamine In hexane at -5 - 10℃; for 12h; Inert atmosphere; | 3 [Example 3] Preparation of 1-palmitoyl-2-linoleoyl-3-acetyl Glycerol To a 250 mL 3-neck round flask, 7.67 g of linoleic acid, 80 mL of normal hexane and 3.31 g of pivaloyl chloride were added, and the reactant was cooled to -5 to 10° C. and 5.97 g of triethylamine was added dropwise. After adding 10 g of 1-palmitoyl-3-acetyl glycerol and 0.328 g of 4-dimethylaminopyridine to the reactant, the reactant was reacted for 12 hours while stirring under nitrogen gas. (0025) After the reaction was completed, 40 mL of purified water was added to the reactant, and the aqueous layer was layer-separated to obtain a washed organic layer. To the separated organic layer, a mixed solution of 27 mL of methanol and 13.5 mL of 0.1N KOH was added, washed twice, and further washed with 40 mL of a mixed solution of 95 vol % methanol purified water, washed with 10 mL of 0.1 vol % hydrochloric acid, and then washed with 40 mL of an aqueous 0.05 weight % sodium hydrogen carbonate solution. 8 g of activated carbon, 10 g of magnesium sulfate and 10 g of clay were added to the washed organic layer and the organic layer was stirred for 2 hours while maintaining 0 to 5° C. Then the activated carbon was filtered and the organic layer was washed with normal hexane which is cooled to -10° C. to obtain 8.5 g of 1-palmitoyl-2-linoleoyl-3-acetyl glycerol in the form of a pale yellow oil (Yield: 74.8%). |
30% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; | |
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.9% | With pseudomonas lipase In lithium hydroxide monohydrate at 40℃; for 24h; Enzymatic reaction; | |
85% | With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 18h; Inert atmosphere; | 3 EDC HCI (624 mg, 3.25 mmol, 2.5 equiv), DMAP (16 mg, 0.13 mmol, 0.1 equiv) and cholesterol (500 mg, 1.30 mmol, 1 equiv) were added to a solution of linoleic acid (728 l, 2.35 mmol, 1 .8 equiv) in anhydrous DCM at 0°C and under nitrogen atmosphere. The reaction was stirred at room temperature for 18 hours. The solvent was then removed, and the residue was dissolved in ethyl ether. The organic phase was washed with a saturated solution of Na2COs, 10% HCI and brine. The organic phase was dried on anhydrous Na2SO4 and concentrated. The crude was purified on silica gel using hexane/AcOEt 9:1 to give 700 mg (yield 85%) of a white waxy solid.The identity and purity of the white waxy solid were confirmed by spectroscopy. Pf 1H-NMR (400 MHz, Chloroform-d) 5 0.70 (s, 3H, H-18), 0.89 (dd, J = 1.8, 6.6 Hz, 6H), 0.91 - 1.63 (m, 30H), 1.67 (sxt, J = 7.4 Hz, 2H), 1.86 (tdd, J = 4.4, 7.7, 15.3 Hz, 3H), 2.01 (ddt, J = 4.3, 16.7, 20.1 Hz, 2H), 2.25 (t, J = 7.4 Hz, 2H ), 2.33 (dd, J = 1 .7, 7.3 Hz, 2H), 4.57 - 4.72 (m, 1 H), 5.39 (dt, J = 1.7, 3.3 Hz, 1 H).13C NMR (100 MHz, Chloroform-d) 5 11.96, 14.11 , 18.89,19.37, 21.13, 22.65, 22.68, 23.93, 24.56, 25.13, 25.67, 27.17, 27.23, 28.17,28.38, 29.02, 29.05, 29.13, 29.43, 31.53, 32.06, 32.10, 32.1 1 , 34.78, 35.84,36.19, 36.77, 37.06, 38.40, 39.41 , 39.79, 42.48, 50.23, 56.50, 56.80, 73.85,122.68, 128.37, 128.42, 130.09, 130.18, 139.92, 173.48. |
85% | With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 18h; Inert atmosphere; | 3.a EDC HCI (624 mg, 3.25 mmol, 2.5 equiv), DMAP (16 mg, 0.13 mmol, 0.1 equiv) and cholesterol (500 mg, 1.30 mmol, 1 equiv) were added to a solution of linoleic acid (728 l, 2.35 mmol, 1 .8 equiv) in anhydrous DCM at 0°C and under nitrogen atmosphere. The reaction was stirred at room temperature for 18 hours. The solvent was then removed, and the residue was dissolved in ethyl ether. The organic phase was washed with a saturated solution of Na2COs, 10% HCI and brine. The organic phase was dried on anhydrous Na2SO4 and concentrated. The crude was purified on silica gel using hexane/AcOEt 9:1 to give 700 mg (yield 85%) of a white waxy solid.The identity and purity of the white waxy solid were confirmed by spectroscopy. Pf 1H-NMR (400 MHz, Chloroform-d) 5 0.70 (s, 3H, H-18), 0.89 (dd, J = 1.8, 6.6 Hz, 6H), 0.91 - 1.63 (m, 30H), 1.67 (sxt, J = 7.4 Hz, 2H), 1.86 (tdd, J = 4.4, 7.7, 15.3 Hz, 3H), 2.01 (ddt, J = 4.3, 16.7, 20.1 Hz, 2H), 2.25 (t, J = 7.4 Hz, 2H ), 2.33 (dd, J = 1 .7, 7.3 Hz, 2H), 4.57 - 4.72 (m, 1 H), 5.39 (dt, J = 1.7, 3.3 Hz, 1 H).13C NMR (100 MHz, Chloroform-d) 5 11.96, 14.11 , 18.89,19.37, 21.13, 22.65, 22.68, 23.93, 24.56, 25.13, 25.67, 27.17, 27.23, 28.17,28.38, 29.02, 29.05, 29.13, 29.43, 31.53, 32.06, 32.10, 32.1 1 , 34.78, 35.84,36.19, 36.77, 37.06, 38.40, 39.41 , 39.79, 42.48, 50.23, 56.50, 56.80, 73.85,122.68, 128.37, 128.42, 130.09, 130.18, 139.92, 173.48. |
With sulfuric acid In dichloromethane Reflux; | Synthesis of DCPLA-cholesteryl ester and cholesteryl linoleate DCPLA (1 g), cholesterol (1 g), CH2CI2 (20 ml), and concentrated H2S04 (1 μΙ) were combined and refluxed overnight. The product was washed with sodium phosphate (pH 7.0, 5 ml) and purified by flash chromatography to yield the DCPLA-cholesteryl ester. Linoleic acid (1 g), cholesterol (1 g), CH2CI2 (20 ml), and concentrated H2S0 (20 μΙ) were combined and refluxed overnight. The product was washed with sodium phosphate (pH 7.0, 5 ml) and purified by flash chromatography to yield the cholesteryl linoleate. | |
With sulfuric acid In dichloromethane Reflux; | Synthesis of DCPLA-cholesteryl ester and cholesteryl linoleate: Linoleic acid (1 g), cholesterol (1 g), CH2CI2 (20 ml), and concentrated H2S0 (20 μΙ) were combined and refluxed overnight. The product was washed with sodium phosphate (pH 7.0, 5 ml) and purified by flash chromatography to yield the cholesteryl linoleate. | |
With sulfuric acid | Synthesis of DCPLA-Cholesteryl Ester and Cholesteryl Linoleate: Linoleic acid (1 g), cholesterol (1 g), CH2Cl2 (20 ml), and concentrated H2SO4 (20 μl) were combined and refluxed overnight. The product was washed with sodium phosphate (pH 7.0, 5 ml) and purified by flash chromatography to yield the cholesteryl linoleate. Alternative Synthesis of DCPLA-Cholesteryl Ester: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With lipase from Pseudomonas Cepacia In tetrahydrofuran; di-isopropyl ether at 60℃; for 240h; | |
With lipase from Pseudomonas Cepacia In tetrahydrofuran; di-isopropyl ether at 60℃; for 240h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Stage #1: linoleic acid With soybean lipoxygenase; oxygen Stage #2: With sodium tetrahydridoborate Further stages.; | |
With borate buffer; soybean lipoxygenase; oxygen at 4℃; for 0.5h; | ||
Multi-step reaction with 2 steps 1: soybean lipoxygenase 1 / 21 - 23 °C / pH 9 / aq. buffer; Enzymatic reaction 2: sodium tetrahydridoborate; potassium dihydrogen orthophosphate; sodium chloride / diethyl ether / pH 9 / aq. buffer |
With Myxococcus xanthus lipoxygenase In aq. buffer at 30℃; for 0.05h; Enzymatic reaction; regiospecific reaction; | A 2.8 Specific activity and kinetic parameters General procedure: The specific activity of M. xanthus LOX for PUFA substrates was determined by measuring the increase in absorbance at 234nm using a Beckman Coulter DU-700 spectrophotometer (Brea, CA, USA) after incubation at 30°C in 50mM EPPS (pH8.5) buffer containing 0.1mM substrate and 0.6-3.6μgmL-1 enzyme for 3min. Only the part of each reaction showing a linear correlation between product concentration and time and the extinction coefficient of 25,000M-1cm-1 for conjugated fatty acids was used to calculate enzyme activity. One unit of LOX activity was defined as the amount of enzyme required to produce 1μmol per min HpFAs at 30°C and pH8.5. Specific activity, which was determined with 1mL reaction volume, was defined as the amount of product per amount of protein per unit reaction time. To determine kinetic parameters, the reactions were performed at 30°C in 50mM EPPS (pH8.5) buffer by varying the amounts of PUFAs from 10 to 900μM for 1min, and enzyme activity was determined by the polarographic assay using a Clark-type electrode (YSI 5300A, Yellow Springs, OH, USA). Kinetic parameters, Km (mM) and kcat (min-1), were calculated using the enzyme concentration and Hanes-Woolf plot derived from the Michaelis-Menten equation. To calculate the catalytic constant kcat, the amount of protein was divided by total molecular mass. | |
With rac-cysteine; N-[2-hydroxyethyl]piperazine-N'-[3-propanesulfonic acid]; Archangium violaceum linoleic acid 13S-LOX lipoxygenase In aq. buffer at 30℃; for 0.166667h; Green chemistry; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; | 4.2.2. Acylation of 2 with acid and DCC General procedure: A solution of DCC (824 mg, 4 mmol) in dry CH2Cl2 (7 mL) was added dropwise to a stirred and ice-cooled solution of (9Z,12Z)-n-C5H11CHCHCH2CHCH(CH2)7CO2H (linoleic acid, 560 mg, 2 mmol), (+/-)-2 (264 mg, 2 mmol), and DMAP (15 mg, 0.12 mmol) in dry CH2Cl2 (10 mL) over 30 min at 0-5 °C. Stirring was continued for 1 h at 0-5 °C, and the mixture was left to stand overnight at room temperature. It was then diluted with hexane and filtered through Celite. The Celite layer was washed with hexane. The combined filtrate and washings were concentrated in vacuo. The residue was chromatographed over SiO2 (15 g). Elution with hexane/EtOAc (20:1) gave 836.5 mg (quant.) of (+/-)-3e contaminated with DCC, which could be removed in the next step. Preparation of 3b and 3e was executed by the above procedure. |
With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Stage #1: linoleic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: With ammonia In dichloromethane for 12h; | (21) General Procedure for Amide Coupling General procedure: To a stirred solution of the fatty acid (1.0 mmol, 1.0 equiv.) inCH2Cl2 (5 mL) was added CDI (0.178 g, 1.1 mmol, 1.1 equiv.).After 30 min at room temperature, the amine (1.1 mmol, 1.1equiv.) was added. After 12 h, CH2Cl2 (25 mL) was added, followedby saturated aqueous NH4Cl. The mixture was acidified topH 2 by addition of HCl, the organic phase was separated, andthe aqueous layer was further extracted with CH2Cl2 (3 × 10mL). The organic phases were combined, dried over Na2SO4, filtered,and concentrated in vacuo, to give the amide. |
Multi-step reaction with 2 steps 1: (COCl)2 / CH2Cl2 / 20 °C 2: aq. NH3 / 0 °C | ||
Multi-step reaction with 2 steps 1: (COCl)2, DMF / benzene / 3 h / Ambient temperature 2: 95 percent / NH3(gas) / CH2Cl2 / 1 h / Ambient temperature |
Multi-step reaction with 2 steps 1: PCl3 2: NH3 / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 89 percent / N,N'-diisopropylethylamine / CHCl3 / 1 h / 0 °C 2: 93 percent / t-BuOK / 6 h / 25 °C | ||
Multi-step reaction with 2 steps 1: CHCl3 / 1 h / 45 °C 2: 4 h / Ambient temperature | ||
Multi-step reaction with 3 steps 1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 16 h / 0 - 20 °C 2: triphenylphosphine; lithium iodide / acetone / 20 °C / Sealed tube; Microwave irradiation 3: triethylamine; (2-morpholino-N-(quinolin-8-yl)acetamido)nickel(II) chloride; (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; potassium fluoride; propyl cyanide / N,N-dimethyl-formamide / 20 h / 20 °C / Inert atmosphere; Sealed tube; Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; ethanol; water; at 150 - 215℃; under 7500.75 - 24002.4 Torr; for 0 - 6h;Product distribution / selectivity; | Example 1; A comparison was carried out between reactions carried out in 96% ethanol (according to the invention), and 99.9% ethanol (dry ethanol, comparative example). Both reactions were catalysed by sodium hydroxide, which was used in the form of dry pellets. Safflower oil was used as source for linoleic acid. The sample removed at t=0 hr is the first sample taken when the desired temperature was reached. The reaction mixture was analysed by the fatty acid methyl ester (FAME) method using gas chromatography. The results for the process using 96% ethanol are set out in the following table: The results for the process using 99.9% ethanol are set out in the following table When 96% ethanol was used with addition of extra water, 96.6% of C18:2c was converted in 6 hours. Using dry ethanol gave a conversion of 99.5% in 6 hours. However, the reaction mixture with the lower water content produced higher amounts of the conjugated trans, tans isomer, was very viscous and difficult to stir and to remove samples.; Example 4; COMPARATIVE EXAMPLE; A comparative example was carried out to show the formation of trans, trans isomers at temperatures outside the claimed range. Saffower oil (200 g), caustic soda (45 g) and 95-97% ethyl alcohol (450 ml) were heated under a pressure of 30-32 bar at 210-215 C. for 4 hours. Samples of the reaction mixture were taken at the start of the reaction and at 2 and 4 hours. The reaction mixture was analysed by the fatty acid methyl ester (FAME) method using gas chromatography. The results for the trans, trans conjugated isomer of CLA were as follows:; Example 1; A comparison was carried out between reactions carried out in 96% ethanol (according to the invention), and 99.9% ethanol (dry ethanol, comparative example). Both reactions were catalysed by sodium hydroxide, which was used in the form of dry pellets. Safflower oil was used as source for linoleic acid. The sample removed at t=0 hr is the first sample taken when the desired temperature was reached. The reaction mixture was analysed by the fatty acid methyl ester (FAME) method using gas chromatography. The results for the process using 96% ethanol are set out in the following table: The results for the process using 99.9% ethanol are set out in the following table When 96% ethanol was used with addition of extra water, 96.6% of C18:2c was converted in 6 hours. Using dry ethanol gave a conversion of 99.5% in 6 hours. However, the reaction mixture with the lower water content produced higher amounts of the conjugated trans, tans isomer, was very viscous and difficult to stir and to remove samples. | |
With potassium hydroxide; ethanol; water; at 150℃; under 7500.75 - 9000.9 Torr; for 0 - 6h;Product distribution / selectivity; | Example 2; An experiment was carried out to compare processes carried out using ethanol (EtOH) (according to the invention) and propylene glycol (MPG) (comparative example). These reactions were catalysed by potassium hydroxide. Safflower oil was used as source for linoleic acid. The water in the system is from the potassium hydroxide used. Reaction Conditions: The results of FAME analysis of the reaction in ethanol were as follows: The results of FAME analysis of the reaction in propylene glycol were as follows: When 96% ethanol was used as solvent, 99.5% of C18:2c was converted in 2 hours. Using propylene glycol gave a conversion of 90.7% in 2 hours.; Example 3; A series of five experiments was carried out using safflower oil (300 g)>potassium hydroxide pellets and 96% ethanol (250 ml) as the solvent. The amount of potassium hydroxide was varied (72.6 g, 77.5 g, 85.3 g, 103 g and 120.6 g). Since the pellets used contain about 15% water, the water content also varied as a result of varying the amount of potassium hydroxide. The amount of water used in the examples was 10.9%, 11.3%, 11.9%, 13.3% and 14.6%. A measurement of the conversion of linoleic acid showed that the rate of reaction increased with increasing water content, at these levels of water content. | |
With potassium hydroxide; water; In propylene glycol; at 150℃; under 7500.75 - 9000.9 Torr; for 0 - 6h;Product distribution / selectivity; | Example 2; An experiment was carried out to compare processes carried out using ethanol (EtOH) (according to the invention) and propylene glycol (MPG) (comparative example). These reactions were catalysed by potassium hydroxide. Safflower oil was used as source for linoleic acid. The water in the system is from the potassium hydroxide used. Reaction Conditions: The results of FAME analysis of the reaction in ethanol were as follows: The results of FAME analysis of the reaction in propylene glycol were as follows: When 96% ethanol was used as solvent, 99.5% of C18:2c was converted in 2 hours. Using propylene glycol gave a conversion of 90.7% in 2 hours. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.5% | With dicyclohexyl-carbodiimide In hexane at 20℃; for 4h; | D-2 D-2. Preparation of opticallv active l-palmitoyl-2-linoleoyl-3-acetylglycerol (PLA); [124] 232. 4g of optically active 1-palmitoyl-3-acetyl glycerol obtained from the above process C-4 was added into 1, 162mol of hexane, and 183. 7g of linoleic acid and 141. 57g of dicyclohexylcarbodiimide (DCC) were added thereto at room temperature. 0. 76g of dimethylamino pyridine (DMAP) was added to the reaction mixture, and the reaction mixture was stirred for 4 hours at the same temperature. Then 5.61g of H2O was added thereto, and the reaction mixture was stirred for additional 1 hour and filtered. The filtrate was separated and purified with a column chromatography in which the stationary phase was silica gel Si-60 (230 to 400 mesh) and the eluent was the mixture of hexane with ethylacetate (the volume ratio of hexane and ethylacetate is 18 : 1) to obtain 322. 2g of the target material (theoretical amounts : 395. 4g, yield : 81. 5%). The obtained optically active l-palmitoyl-2-linoleoyl-3-acetylglycerol was analyzed by H-NMR, and the results and other property are as follows. [125] (1) (R)-enantiomer :'H NMR (250MHz, CDC1) : 8 0. 85-0. 9 (m, 6H), 1. 20-1. 31 (m, 38H), 1. 61 (m, 4H), 2. 03 (m, 4H), 2. 07 (s, 3H), 2. 37 (t, J=7. 5Hz, 2H), 2. 33 (t, J=7. 5Hz, 2H), 2. 77 (m, lH), 4. 14 (dd, J=5. 95, 11. 8Hz, 2H), 4. 29 (ddd, J=4. 14, 11. 8, 12. 8Hz, 2H), 5. 26 (m, lH) [126] (2) (S)-enantiomer :'H NMR (250MHz, CDC1) : 8 0. 84-0. 93 (m, 6H), 1. 21-1. 31 (m, 38H), 1. 60 (m, 4H), 2. 02 (m, 4H), 2. 07 (s, 3H), 2. 38 (t, J=7. 5Hz, 2H), 2. 33 (t, J=7. 5Hz, 2H), 2. 76 (m, lH), 4. 15 (dd, J=5. 95, 11. 8Hz, 2H), 4. 30 (ddd, J=4. 14, 11. 8, 12. 8Hz, 2H), 5. 25 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; dicyclohexyl-carbodiimide In n-heptane at 20℃; for 3h; | 3 [Example 3] Preparation of l-palmitoyl-2-linoleoyl-3-trityl- glycerol; [62] l-palmitoyl-3-tritylglycerol (57.3g), which was obtained in Example 1, heptane(300ml), linoleic acid (29.4g) and dimethylaminopyridine (0.122g) were added into IL reactor. Dicyclohexylcarbodiimide (21.7g) was added into the reactor, and then the reaction mixture was stirred for 3 hours at room temperature. Dicyclohexylurea was filtered to obtain heptane solution of l-palmitoyl-2-linoleoyl-3-trityl-glycerol (expected yield: 100%) (1H NMR (400MHz, CDCl ): 0.92 - 0.95(m, 6H), 1.33 - 1.43 (m,36H), 1.60(m,2H), 1.69(m,2H), 2.09 - 2.11(m, 4H), 2.26(t,2H), 2.27(t,2H), 2.83(t,2H), 3.31(m,2H), 4.24 - 4.42(m,4H), 5.31 - 5.41(m,5H), 7.21 - 7.49 (m, 15H)} [63] |
With dicyclohexyl-carbodiimide In n-heptane at 20℃; for 3h; | 3 Preparation of 1-palmitoyl-2-linoleoyl-3-trityl-glycerol 1-palmitoyl-3-tritylglycerol (57.3 g), which was obtained in Example 1, heptane (300 ml), linoleic acid (29.4 g) and dimethylaminopyridine (0.122 g) were added into 1 L reactor. Dicyclohexylcarbodiimide (21.7 g) was added into the reactor, and then the reaction mixture was stirred for 3 hours at room temperature. Dicyclohexylurea was filtered to obtain heptane solution of 1-palmitoyl-2-linoleoyl-3-trityl-glycerol (expected yield: 100%) {1H NMR (400 MHz, CDCl3): δ 0.92-0.95 (m, 6H), 1.33-1.43 (m, 36H), 1.60 (m, 2H), 1.69 (m, 2H), 2.09-2.11 (m, 4H), 2.26 (t, 2H), 2.27 (t, 2H), 2.83 (t, 2H), 3.31 (m, 2H), 4.24-4.42 (m, 4H), 5.31-5.41 (m, 5H), 7.21-7.49 (m, 15H)}. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; dicyclohexyl-carbodiimide In n-heptane at 20℃; for 3h; | 4 [Example 4] Preparation of 1 -palmitoyl-2-linoleoyl-3-t-butyl-dimethylsilyl-glvcerol; [65] l-palmitoyl-3-t-butyldimethylsilyl-glycerol (44.4g), which was obtained inExample 2, heptane (225ml), linoleic acid(29.4g) and dimethylaminopyridine(0.122g) were added into IL reactor. Dicyclohexylcarbodiimide (21.7g) was added into the reactor, and then the reaction mixture was stirred for 3 hours at room temperature. Dicyclohexylurea was filtered to obtain heptane solution of l-palmitoyl-2-linoleoyl-3-t-butyl-dimethylsilyl-glycerol (expected yield: 100%) ( IH NMR (400MHz, CDCl3): 0.76 - 0.81(m, 21H), 1.16 - 1.27 (m,36H), 1.50 - 1.52(m,4H), 1.95(q,4H), 2.17 - 2.21(m, 4H), 2.65(t,2H), 3.62(d,2H), 4.02 - 4.28(m,4H), 4.96 - 5.27(m,5H)}. |
With dicyclohexyl-carbodiimide In n-heptane at 20℃; for 3h; | 4 Preparation of 1-palmitoyl-2-linoleoyl-3-t-butyl-dimethylsilyl-glycerol 1-palmitoyl-3-t-butyldimethylsilyl-glycerol (44.4 g), which was obtained in Example 2, heptane (225 ml), linoleic acid (29.4 g) and dimethylaminopyridine (0.122 g) were added into 1 L reactor. Dicyclohexylcarbodiimide (21.7 g) was added into the reactor, and then the reaction mixture was stirred for 3 hours at room temperature. Dicyclohexylurea was filtered to obtain heptane solution of 1-palmitoyl-2-linoleoyl-3-t-butyl-dimethylsilyl-glycerol (expected yield: 100%) {1H NMR (400 MHz, CDCl3): δ 0.76-0.81 (m, 21H), 1.16-1.27 (m, 36H), 1.50-1.52 (m, 4H), 1.95 (q, 4H), 2.17-2.21 (m, 4H), 2.65 (t, 2H), 3.62 (d, 2H), 4.02-4.28 (m, 4H), 4.96-5.27 (m, 5H)}. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.3% | Stage #1: linoleic acid; 2,3,5-Trimethyl-1,4-benzoquinone With silver nitrate In water; acetonitrile at 70℃; Stage #2: With dipotassium peroxodisulfate In water; acetonitrile at 70℃; for 3h; | 2A Example 2A To a 250 ml round bottom flask was added 2,3,5-trimethyl-[1,4]benzoquinone (1.50 g, 9.98 mmole), linolenic acid (2.94 g, 10.4 mmole), and silver nitrate (1.83 g, 10.8 mmole) in a 1:1 mixture of water and acetonitrile (100 ml). The solution was heated to 70° C. under argon and an aqueous solution of K2S2O8 (2.55 g, 11.5 mmole in 50 ml water) was added dropwise to the homogenous solution over 2.5 hours using a syringe pump. The reaction mixture was allowed to stir an additional 30 minutes at 70° C., then cooled to room temperature. To the mixture was added MTBE (200 ml) and water (100 ml). The organic layer was separated and washed with saturated NaHCO3 (100 ml), then brine (2*200 ml). The MTBE solution was dried over sodium sulfate then concentrated to a yellow oil. The crude product, which contained residual unreacted starting quinone by TLC, was further purified by silica gel chromatography (120 g, 0-30% EtOAc:heptane) to give pure 2-heptadeca-8,11-dienyl-3,5,6-trimethyl-[1,4]benzoquinone (210; 0.474 g, 12.3%) as a yellow oil. 1H NMR (400 MHz; d6-DMSO; ppm): 5.36-5.26 (m, 4H), 2.73 (t, J=5.6 Hz, 2H), 2.42-2.38 (m, 2H), 2.02-1.93 (m, 4H). 1.95 (s, 3H), 1.93 (s, 6H). 1.34-1.22 (m, 16H), 0.84 (t, J=7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of the linoleic acid (25 g, 89.1 mmol) in anhydrous DMF (60 mL), diisopropyl ethylamine (17 mL, 100 mml) was added at room temperature with stirring followed by <strong>[623-57-4]3-(dimethylamino)-1,2-propanediol</strong> (4.8 g , 40.5 mmol) and EDCI (17.25 g, 89.9 mmol) and the mixture was stirred at room temperature overnight. The TLC of the reaction mixture (eluent 20percent EtOAc in hexanes) showed the completion of the reaction. The reaction mixture was poured into ice water and extracted with ethyl acetate (2 x <n="133"/>100 mL). The combined organic layers were washed with water (100 mL), saturated NaHCO3 (100 mL) and dried over Na2SO4. Concentration of the organic layer provided the crude product which was purified by column chromatography (silica gel, eluent: 20percent EtOAc in hexanes). The fractions containing pure product was pooled and concentrated. The pure ester was isolated as a clear liquid (5.7 g, 22percent). MS m/z 645 (M+H). 1H NMR CDCl3 delta 0.88 (t,J= 6.3Hz, 6H), 1.20-1.39 (m, 28H), 1.61 (t, J = 4.9 Hz, 12H), 2.03-2.08 (m, 8H), 2.26-2.38 (m, 10H), 2.44-2.56 (m, 2H), 2.76 (t, J= 6.3 Hz, 4 H), 4.09 (dd, J= 6.1 Hz 11.9 Hz, 1H), 4.36 (dd, J= 3.3 11.9 Hz, 1H), 5.29-5.34 (m, 1H), 5.34-5.41 (m, 8H). 13C NMR CDCl3 delta 14.30, 22.79, 25.08, 25.10, 25.83, 27.40, 29.26, 29.30, 29.34, 29.42, 29.55, 29.83, 31.73, 34.32, 34.58, 46.01, 59.37, 64.02, 128.08, 128.24, 130.21, 130.42, 173.39, 173.65. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.84 g (87%) | In methanol; n-heptane; water; ethyl acetate; toluene; | Example 1 Preparation of <strong>[58186-27-9]Idebenone</strong> Linoleate (1a)(EX00011-037) <strong>[58186-27-9]Idebenone</strong> (2a, R=R1=Me, n=9; 547 mg; 1.6 mmol) was dissolved in 10 mL of toluene. Linoleic acid (2.18 g; 4.9 equiv) was added followed by 641 mg of 4A molecular sieves and 309 mg of Novozym 435. The reaction mixture was stirred at ambient temperature for 2 days, at which point tlc analysis (1:1 ethyl acetate:heptane eluant) indicated no remaining idebenone. The solids were removed by filtration and the precipitate washed with toluene. The combined filtrate and washes were concentrated at reduced pressure. The residue was dissolved in heptane (22 mL) and washed with a mixture of 11 mL of methanol and 11 mL of 10% aqueous potassium carbonate. The organic layer was further washed with a mixture of 11 mL of methanol, 4 mL of saturated sodium bicarbonate, and 7 mL of water. The organic layer was then dried with sodium sulfate and concentrated to afford 0.84 g (87%) of 1a (R=R1=Me, n=9). 1H NMR (CDCl3) delta5.40-5.30 (m, 4H); 4.049 (t, 2H, J=6.87 Hz); 3.988 (s, 6H); 2.768 (t, 2H, J=5.77 Hz); 2.45 (m, 2H); 2.288 (t, 2H, J=7.42 Hz); 2.08-2.01 (m, 3H); 2.009 (s, 3H); 1.64-1.57 (m, 3H); 1.40-1.29 (m, 30H); 0.89 (t, 3H, J=6.60 Hz). |
0.84 g (87%) | silica gel; In methanol; n-heptane; water; ethyl acetate; toluene; | EXAMPLE 1 Preparation of <strong>[58186-27-9]Idebenone</strong> Linoleate (1a)(EX00011-037) <strong>[58186-27-9]Idebenone</strong> (2a, R=R1=Me, n=9; 547 mg; 1.6 mmol) was dissolved in 10 mL of toluene. Linoleic acid (2.18 g; 4.9 equiv) was added followed by 641 mg of 4 A molecular sieves and 309 mg of Novozym 435. The reaction mixture was stirred at ambient temperature for 2 days, at which point tlc analysis (1:1 ethyl acetate:heptane eluant) indicated no remaining idebenone. The solids were removed by filtration and the precipitate washed with toluene. The combined filtrate and washes were concentrated at reduced pressure. The residue was dissolved in heptane (22 mL) and washed with a mixture of 11 mL of methanol and 11 mL of 10% aqueous potassium carbonate. The organic layer was further washed with a mixture of 11 mL of methanol, 4 mL of saturated sodium bicarbonate, and 7 mL of water. The organic layer was then dried with sodium sulfate and concentrated to afford 0.84 g (87%) of 1a (R=R1=Me, n=9). 1H NMR (CDCl3) delta 5.40-5.30 (m, 4H); 4.049 (t, 2H, J =6.87 Hz); 3.988 (s, 6H); 2.768 (t, 2H, J=5.77 Hz); 2.45 (m, 2H); 2.288 (t, 2H, J=7.42 Hz); 2.08-2.01 (m, 3H); 2.009 (s, 3H); 1.64-1.57 (m, 3H); 1.40-1.29 (m, 30H); 0.89 (t, 3H, J=6.60 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With novozym 435; In toluene; at 20℃; for 48h;4A molecular sieves; | Example 1 :Preparation of ldebenone Linoleate (1a)(EX00011-037) ldebenone (2a, R = R1 = Me, n= 9; 547 mg; 1.6 mmol) was dissolved in10 mL of toluene. Linoleic acid (2.18 g; 4.9 equiv) was added followed by 641 mg of 4A molecular sieves and 309 mg of Novozym 435. The reaction mixture was stirred at ambient temperature for 2 days, at which point tic analysis (1 :1 ethyl acetate:heptane eluant) indicated no remaining idebenone. The solids were removed by filtration and the precipitate washed with toluene. The combined filtrate and washes were concentrated at reduced pressure. The residue was dissolved in heptane (22 mL) and washed with a mixture of11 mL of methanol and 11 mL of 10% aqueous potassium carbonate. The organic layer was further washed with a mixture of 11 mL of methanol, 4 mL of saturated sodium bicarbonate, and 7 mL of water. The organic layer was then dried with sodium sulfate and concentrated to afford 0.84 g (87%) of 1a (R = R1 = Me, n= 9).1H NMR (CDCI3) delta 5.40-5.30 (m, 4H); 4.049 (t, 2H, J = 6.87 Hz); 3.988 (s, 6H); 2.768 (t, 2H, J = 5.77 Hz); 2.45 (m, 2H); 2.288 (t, 2H1 J = 7.42 Hz); 2.08- 2.01 (m, 3H); 2.009 (s, 3H); 1.64-1.57 (m, 3H); 1.40-1.29 (m, 30H); 0.89 (t, 3H, J = 6.60 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; In toluene; at 20℃; for 2 - 50h;Enzymatic reaction;Product distribution / selectivity; | Example 4; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 71.7% conversion to retinyl linoleate with 17.7% retinyl acetate and 10.6% retinol. Stirring for an additional 2 days afforded no further change.; Example 4; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 71.7% conversion to retinyl linoleate with 17.7% retinyl acetate and 10.6% retinol. Stirring for an additional 2 days afforded no further change.; Example 9; Preparation of Retinyl Linoleate with 5 Equiv of Linoleic Acid in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (140 mg; 5.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 87.4% conversion to retinyl linoleate with 9.2% retinyl acetate and 3.4% retinol. Stirring overnight afforded no further change.; Example 15; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid and Product Isolation; Retinyl acetate (4.11 g; 12.5 mmol) and linoleic acid (7.01 g; 25.0 mmol; 2.0 equiv) were dissolved in 35 mL of toluene. Novozyme 435 (1.0 g) and dried Amberlyst A-21 (2.1 g) were added, and the reaction mixture was evacuated and filled with nitrogen ten times. The reaction mixture was stirred in the dark at ambient temperature for 5.5 h, at which point HPLC analysis indicated 90.3% conversion to retinyl linoleate (9.1% retinyl acetate and 0.6% retinol). The reaction mixture was filtered and concentrated, then concentrated twice with heptane (10 mL each). The residue was dissolved in heptane (50 mL) and washed with 2×80 mL with a 1:1 mixture of 10% aqueous potassium carbonate and methanol. The organic layer was washed further with a mixture of saturated sodium bicarbonate (10 mL), water (30 mL), and methanol (40 mL), dried (sodium sulfate) and concentrated to afford 5.14 g (75%) of a yellow oil. A portion of this material (4.00 g) was dissolved in 40 mL of heptane and washed with 20 mL of methanol. The heptane layer was concentrated to afford 3.77 g (71% overall) of retinyl linoleate. Analysis of this product indicated 90.9% retinyl linoleate (HPLC area percent), 0.26 wt % linoleic acid, and 0.06 wt % retinol. The initial aqueous extracts (using a 1:1 mixture of 10% aqueous potassium carbonate and methanol) were acidified to pH 1 with 25 mL of 3 M HCl. The resulting mixture was extracted with 20 mL of heptane. The organic solution was dried with sodium sulfate and concentrated to afford 3.91 g (56% of initial charge) of recovered linoleic acid, which was suitable for re-use. |
With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); In toluene; at 20 - 50℃; for 1 - 2h;Enzymatic reaction;Product distribution / selectivity; | Example 1; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred and heated at 50 C. for 1 h, at which point a sample was removed and analyzed by HPLC, indicating 49.8% conversion to retinyl linoleate with 39.8% retinyl acetate and 10.4% retinol.HPLC (4.6×150 mm Zorbax SB-C8 column [Agilent], 3.5mu thickness, methanol eluent, detection at 350 nm): tR 4.77 min (retinyl linoleate); tR 2.32 min (retinyl acetate); tR 2.08 min (retinol).; Example 5; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (56 mg; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at ambient temperature for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 63.4% conversion to retinyl linoleate with 30.5% retinyl acetate and 4.8% retinol.; Example 8; Preparation of Retinyl Linoleate with 5 Equiv of Linoleic Acid; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (140 mg; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at ambient temperature for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 78.7% conversion to retinyl linoleate with 17.6% retinyl acetate and 3.7% retinol. | |
With Lipozyme TI IM; Amberlyst A-21; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity; | Example 24; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipozyme TI IM in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipozyme TI IM (Novozyme). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 14.6% conversion to retinyl linoleate with 84.7% retinyl acetate and 0.7% retinol. |
With Lipozyme TI IM; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity; | Example 23; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipozyme TI IM; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipozyme TI IM (Novozyme). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 2.0% conversion to retinyl linoleate with 94.9% retinyl acetate and 3.2% retinol. | |
With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlite IRA-95; In toluene; at 20℃; for 2 - 50h;Enzymatic reaction;Product distribution / selectivity; | Example 3; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid in the Presence of Amberlite IRA-95; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlite IRA-95. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 72.3% conversion to retinyl linoleate with 16.3% retinyl acetate and 11.3% retinol. Stirring for an additional 2 days afforded no further change. | |
With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; In acetonitrile; at 20℃; for 23h;Enzymatic reaction; Sonication;Product distribution / selectivity; | Example 12; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid in Acetonitrile with Amberlyst A-21; Retinyl acetate (500 mg; 1.52 mmol) was dissolved in 3.5 mL of acetonitrile with sonication. Dried Amberlyst A-21 (0.25 g) was added. Linoleic acid (850 mg; 3.04 mmol; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 19 h, at which point a sample was removed and analyzed by HPLC, indicating 58.5% conversion to retinyl linoleate with 40.0% retinyl acetate and 1.6% retinol. | |
With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; In limonene.; at 20℃; for 23h;Enzymatic reaction;Product distribution / selectivity; | Example 14; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid in Limonene with Amberlyst A-21; Retinyl acetate (500 mg; 1.52 mmol) and linoleic acid (850 mg; 3.04 mmol; 2.0 equiv) were dissolved in 3.5 mL of limonene. Dried Amberlyst A-21 (0.25 g) and Novozyme 435 (120 mg) were added and the reaction mixture was stirred at RT for 23 h, at which point a sample was removed and analyzed by HPLC, indicating 90.3% conversion to retinyl linoleate with 8.5% retinyl acetate and 1.2% retinol. | |
With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); In vegetable oil; toluene; at 50℃; for 1h;Enzymatic reaction;Product distribution / selectivity; | Example 7; Preparation of Retinyl Linoleate in Vegetable Oil with 2 Equiv of Linoleic Acid; Retinyl acetate (52% in vegetable oil, 63 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (56 mg; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred and heated at 50 C. for 1 h, at which point a sample was removed and analyzed by HPLC, indicating 71.7% conversion to retinyl linoleate with 18.0% retinyl acetate and 10.2% retinol.; Example 10; Preparation of Retinyl Linoleate in Vegetable Oil with 5 Equiv of Linoleic Acid; Retinyl acetate (52% in vegetable oil, 63 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (140 mg; 5.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred and heated at 50 C. for 1 h, at which point a sample was removed and analyzed by HPLC, indicating 83.0% conversion to retinyl linoleate with 10.9% retinyl acetate and 6.2% retinol. | |
With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); In toluene; at 50℃; for 1 - 49h;Enzymatic reaction; Molecular sieve;Product distribution / selectivity; | Example 2; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid in the Presence of Organophilic Molecular Sieves; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 100 mg of organophilic molecular sieves. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred and heated at 50 C. for 1 h, at which point a sample was removed and analyzed by HPLC, indicating 53.2% conversion to retinyl linoleate with 14.4% retinyl acetate and 32.4% retinol. | |
With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); In acetonitrile; at 20℃; for 19h;Enzymatic reaction; Sonication;Product distribution / selectivity; | Example 11; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid in Acetonitrile; Retinyl acetate (500 mg; 1.52 mmol) was dissolved in 3.5 mL of acetonitrile with sonication. Linoleic acid (850 mg; 3.04 mmol; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 19 h, at which point a sample was removed and analyzed by HPLC, indicating 28.7% conversion to retinyl linoleate with 70.8% retinyl acetate and 0.5% retinol. | |
With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); In limonene.; at 20℃; for 23h;Enzymatic reaction;Product distribution / selectivity; | Example 13; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid in Limonene; Retinyl acetate (500 mg; 1.52 mmol) and linoleic acid (850 mg; 3.04 mmol; 2.0 equiv) were dissolved in 3.5 mL of limonene. Novozyme 435 (120 mg) was added and the reaction mixture was stirred at RT for 23 h, at which point a sample was removed and analyzed by HPLC, indicating 65.8% conversion to retinyl linoleate with 32.3% retinyl acetate and 1.9% retinol. | |
With lipase PS-C (from Psuedomonas sp immobilized on ceramic); Amberlyst A-21; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity; | Example 20; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipase PS-C in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0. 10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS-C (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 68.8% conversion to retinyl linoleate with 23.6% retinyl acetate and 7.6% retinol. | |
With lipase PS-C (from Psuedomonas sp immobilized on ceramic); In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity; | Example 19; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic acid Using Lipase PS-C; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS-C (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 46.1% conversion to retinyl linoleate with 48.7% retinyl acetate and 5.2% retinol. | |
With lipase PS-D (from Pseudomonas sp immobilized on diatomaceous earth); Amberlyst A-21; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity; | Example 22; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipase PS in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0. 10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS-D (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 69.2% conversion to retinyl linoleate with 25.8% retinyl acetate and 5.0% retinol. | |
With lipase PS-D (from Pseudomonas sp immobilized on diatomaceous earth); In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity; | Example 21; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipase PS-D; Retinyl acetate (33 mg; 0. 10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS-D (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 35.4% conversion to retinyl linoleate with 63.4% retinyl acetate and 1.2% retinol. | |
With Lipase PS; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity; | Example 18; Preparation of Retinyl Linoleate with 1Equiv of Linoleic Acid Using Lipase PS in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 10.0% conversion to retinyl linoleate with 87.3% retinyl acetate and 2.7% retinol. | |
With Lipase PS; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity; | Example 17; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipase PS; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 1.4% conversion to retinyl linoleate with 97.5% retinyl acetate and 1.1% retinol. |
Yield | Reaction Conditions | Operation in experiment |
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With magnesium; In tetrahydrofuran; diethyl ether; chloroform; water; N,N-dimethyl-formamide; | Example 23A (6Z,9Z,27Z,30Z)-hexatriaconta-6,9,27,30-tetraen-18-one To a suspension of magnesium (0.601 g, 24.71 mmol) in diethyl ether (11 ml) was added dropwise a solution of <strong>[4102-60-7](6Z,9Z)-18-bromooctadeca-6,9-diene</strong> (3.7 g, 11.23 mmol) in diethyl ether (11 ml). The reaction mixture was refluxed for 1 hour then cooled to room temperature to give a solution of the Grignard reagent (9Z,12Z)-octadeca-9,12-dienylmagnesium bromide. To a solution of (9Z,12Z)-octadeca-9,12-dienoic acid (3 g, 10.70 mmol) in CHCl3 (5 ml) was added oxalyl chloride (1.124 ml, 12.84 mmol) and a drop of DMF. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated by rotary evaporation. The residue was taken up in THF (5 ml) and cooled to -78 C. A solution of (9Z,12Z)-octadeca-9,12-dienylmagnesium bromide (10.70 ml, 10.70 mmol) was added dropwise. The reaction mixture was warmed to 0 C. The reaction mixture was quenched in cold water. The mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (4:1 hexanes/dichloromethane). MS (DCI) m/z 530.5 (M+18)+. |
Yield | Reaction Conditions | Operation in experiment |
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96% | Stage #1: linoleic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: ethanolamine In dichloromethane for 12h; | (21) General Procedure for Amide Coupling General procedure: To a stirred solution of the fatty acid (1.0 mmol, 1.0 equiv.) inCH2Cl2 (5 mL) was added CDI (0.178 g, 1.1 mmol, 1.1 equiv.).After 30 min at room temperature, the amine (1.1 mmol, 1.1equiv.) was added. After 12 h, CH2Cl2 (25 mL) was added, followedby saturated aqueous NH4Cl. The mixture was acidified topH 2 by addition of HCl, the organic phase was separated, andthe aqueous layer was further extracted with CH2Cl2 (3 × 10mL). The organic phases were combined, dried over Na2SO4, filtered,and concentrated in vacuo, to give the amide. |
88% | Stage #1: linoleic acid With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 20℃; for 0.166667h; Inert atmosphere; Stage #2: ethanolamine In dichloromethane; acetonitrile at 20℃; Inert atmosphere; | 6 2.3 Synthesis of NAEs (1a-1g) General procedure: These compounds were synthesized according to the procedure described previously with slight modifications (El-Faham and Albericio, 2010) The appropriate acid (0.15 mmol), (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluoro phosphate (COMU, 64.2 mg, 0.15 mmol), and DIPEA (0.05 ml, 0.30 mmol) were dissolved in anhydrous CH2Cl2 (0.5 ml) and CH3CN (2.5 ml) and the resulting orange-red solution was stirred at rt for 10 min under a nitrogen atmosphere. Ethanolamine (3) (0.15 mmol) in CH3CN (0.2 ml) was then injected into the reaction mixture and vigorous stirring at rt was continued until TLC (CH2Cl2/MeOH 98:2) confirmed the completion of the reaction (3-6 h). The reaction mixture was diluted with CH2Cl2 (3 ml) and the resulting mixture was washed with 5% HCl, saturated NaHCO3 and brine. The organic layer was collected, dried over anhydrous Na2SO4, filtered. The solvent was evaporated under reduced pressure and crude purified by flash chromatography. |
85% | With Novozym 435, consisting of immobilized Candida antarctica lipase B In hexane at 40℃; for 6h; Enzymatic reaction; |
85% | With Novozyme 435 immobilized on acrylic resin In hexane at 40℃; | 2.1.1 Synthesis and purification of LEA and LEA-d4 For the synthesis of LEA, we followed a previously documented strategy involving the enzyme Novozym 435 [25]. In brief, we mixed LA and ethanolamine (0.20mmol of each) in a glass vial containing 1ml hexane. The resulting mixture was placed in a thermoconstant girotory shaker (New Brunswick Scientific, USA) and 50mg of Novozym 435 was then added. The mixture was shaken at 200rpm overnight at 40°C. After cooling at room temperature, removal of the solvents was performed under reduced pressure. Purification of LEA was achieved by silica gel chromatography using CHCl3-MeOH (98:2, v/v) to give 54mg (0.17mmol) of LEA (1) (white solid, 85% yield). For the synthesis of LEA-d4, we essentially performed the same steps, but we replaced ethanolamine with ethanolamine-d4. This led to the synthesis of LEA-d4 (2) in good yield (white solid, 85% yield). |
78% | Stage #1: linoleic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: ethanolamine In dichloromethane at 20℃; for 2h; Inert atmosphere; | |
Stage #1: linoleic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In ethyl acetate at 20℃; for 1h; Stage #2: ethanolamine In ethyl acetate at 20℃; for 12h; | 5.2. Synthesis of fatty acid amides General procedure: All fatty acid amides with different acyl chains and amine heads were synthesized using the same procedure but with different precursor compounds. 2-(1H-Benzotriazole-1-yl)-1,2,3,3-tetramethyluronium tetrafluoroborate (TBTU, 1 equiv) was added to a mixture of compound C1 (1 equiv) and triethylamine (TEA, 2 equiv) in EtOAc. After stirring for 1 h at room temperature, isopropylamine (2 equiv) was added and the reaction mixture was stirred for 12 h. The mixture was washed with water, dried and concentrated to give a residue that was purified by reversed-phase HPLC (YMC ODS-H80) eluting with 80% aqueous CH3CN to yield compound 1 (1.5 mg, 63%); |
Yield | Reaction Conditions | Operation in experiment |
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66% | With Candida antarctica lipase B In ethanol; toluene at 110℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
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at 83℃; for 0.25h; | 1 253 g/h of a mixture of oleic acid and linoleic acid with a content of free fatty acids of 100% by weight was passed with 605 g/h of methanol at a temperature of 83° C. and a pressure of 4 bar once with a residence time of 15 min over a fixed catalyst bed composed of 650 ml of acidic ion exchange resin (corresponds to 121 g of catalyst mass (dry)). The catalyst particles had a diameter of 0.8 mm and were immobilized in a fixed bed reactor with a catalyst bed length of 2.08 m. This gives rise to a catalyst hourly space velocity of 2.1 kg of free fatty acid per kg of catalyst and hour, and a superficial velocity of 2.3 mm/s. In the reaction product, an acid content of 2.8% by weight was determined, i.e. a fatty acid conversion of 97.2% was achieved. This gives rise to a space-time yield of fatty-acid methyl ester of 397.1 g per litre of reactor volume and hour. |
Yield | Reaction Conditions | Operation in experiment |
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84.6% | With Sulfated Zirconia type 1 at 140℃; for 4h; Autoclave; | 2.2.1. Esterification of free fatty acid with alcohols General procedure: Esterification was carried out in a stainless steel autoclave reactor equipped with 30 ml of Teflon liner and a Teflon-coated magnetic stirring bar. A mixture of free fatty acid (6.25 mmol), alcohol (7.5 mmol), and catalyst (100 mg) was charged into the Teflon liner. The mixture was heated at 140 °C for 4 h with stirring at 300 rpm. After the reaction, the reaction mixture was cooled to room temperature, and the catalyst was separated from the reaction mixture by centrifuging. To test the recyclability of the catalyst, the catalyst was recovered after the reaction by washing three times with a mixture of hexane and acetone (hexane:acetone = 1:1). Then the catalyst was dried at 100 °C for 24 h. The reaction was repeated five times. |
With 2Al(3+)*3(SO4)(2-)*10H2O=Al2(SO4)3*10H2O at 80℃; for 24h; Neat (no solvent); | ||
With toluene-4-sulfonic acid In toluene at 110℃; Dean-Stark; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: linoleic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: dopamine In dichloromethane for 12h; | (21) General Procedure for Amide Coupling General procedure: To a stirred solution of the fatty acid (1.0 mmol, 1.0 equiv.) inCH2Cl2 (5 mL) was added CDI (0.178 g, 1.1 mmol, 1.1 equiv.).After 30 min at room temperature, the amine (1.1 mmol, 1.1equiv.) was added. After 12 h, CH2Cl2 (25 mL) was added, followedby saturated aqueous NH4Cl. The mixture was acidified topH 2 by addition of HCl, the organic phase was separated, andthe aqueous layer was further extracted with CH2Cl2 (3 × 10mL). The organic phases were combined, dried over Na2SO4, filtered,and concentrated in vacuo, to give the amide. |
Stage #1: linoleic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In ethyl acetate at 20℃; for 1h; Stage #2: dopamine In ethyl acetate at 20℃; for 12h; | 5.2. Synthesis of fatty acid amides General procedure: All fatty acid amides with different acyl chains and amine heads were synthesized using the same procedure but with different precursor compounds. 2-(1H-Benzotriazole-1-yl)-1,2,3,3-tetramethyluronium tetrafluoroborate (TBTU, 1 equiv) was added to a mixture of compound C1 (1 equiv) and triethylamine (TEA, 2 equiv) in EtOAc. After stirring for 1 h at room temperature, isopropylamine (2 equiv) was added and the reaction mixture was stirred for 12 h. The mixture was washed with water, dried and concentrated to give a residue that was purified by reversed-phase HPLC (YMC ODS-H80) eluting with 80% aqueous CH3CN to yield compound 1 (1.5 mg, 63%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: linoleic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In ethyl acetate at 20℃; for 1h; Stage #2: Vanillylamin In ethyl acetate at 20℃; for 12h; | 5.2. Synthesis of fatty acid amides General procedure: All fatty acid amides with different acyl chains and amine heads were synthesized using the same procedure but with different precursor compounds. 2-(1H-Benzotriazole-1-yl)-1,2,3,3-tetramethyluronium tetrafluoroborate (TBTU, 1 equiv) was added to a mixture of compound C1 (1 equiv) and triethylamine (TEA, 2 equiv) in EtOAc. After stirring for 1 h at room temperature, isopropylamine (2 equiv) was added and the reaction mixture was stirred for 12 h. The mixture was washed with water, dried and concentrated to give a residue that was purified by reversed-phase HPLC (YMC ODS-H80) eluting with 80% aqueous CH3CN to yield compound 1 (1.5 mg, 63%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetone; for 2h; | To a solution of 300 mg <strong>[136236-51-6]rasagiline</strong> (1.75 mmol) in 6 ml acetone 0.54 ml (1.75 mmol, 1.0 eq) linoleic acid was added. After stirring for 2 h the solvent was evaporated at 300C in vacuo. Drying in high vacuum led to a brownish oil (0.77 g, 1.75 mmol, quant.).IR: v = 3308.9, 3009.2, 2927.2, 2854.8, 1712.2, 1615.9, 1548.5, 1459.5, 753.8 crrf1. IR indicates protonation of the amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With Novozyme 435; In acetone; at 45℃;Molecular sieve; Enzymatic reaction; | General procedure: To flame dried 3 A molecular sieves, in round bottom flask, was added <strong>[60-81-1]phloridzin</strong> (0.500 g; 1.15 mmol), stearic acid (1.62 g, 5.72 mmol), Novozyme 435 (1.30 g). It was followed by the addition of dry acetone (5 ml) and the mixture was stirred and heated at 45 C for 12-24 h. The progress of reaction was monitored by thin layer chromatography (TLC), followed by staining with anisaldehyde spray reagent and then heating at 110 C. After completion of reaction, it was filtered, evaporated and passed through column chromatography (acetone/toluene; 35:75 to 50:50) to get the pure stearic acid ester (2) of <strong>[60-81-1]phloridzin</strong>. All other reactions followed the same procedure and produced esters 3-7 and 9-14, with yields in the range of 81-98%. The pure compounds were then analyzed by IR, 1H NMR and 13C NMR spectroscopy. All other compounds were prepared by the same method |
89% | With Candida antarctica lipase B; In acetone; at 40 - 45℃; for 3h;Sonication; Molecular sieve; Enzymatic reaction; | General procedure: To flame dried 3 A molecular sieves in an amber color vial, was added <strong>[60-81-1]phloridzin</strong> (0.100 g; 0.23 mmol), butyric acid (0.06 ml,0.69 mmol), Novozyme 435 (0.300 g). It was followed by the addition of dry acetone (5 ml). The reaction was carried out in an ultrasonic bath of 20 kHz/1000W (model 750D, VWR, West Chester, PA, USA) and exposed for 3.5-5 h under ultrasound irradiation alone (for 15-20 min each with 10 min interval in between)and for 2-3.5 h (for 15-20 min each with 10 min interval in between) under ultrasound irradiation coupled with stirring at 40-45 C. The progress of reaction was monitored by thin layer chromatography,followed by staining with anisaldehyde spray reagentand then heating at 110 C. After completion of reaction, it wasfiltered, evaporated and chromatographed (acetone:toluene;35:75-50:50) to get the pure butyric acid ester (2) of <strong>[60-81-1]phloridzin</strong>. All other reactions followed the same procedure and produced esters 2-8 and 9-15, with yields in the range of 81-97%. The pure compounds were then analyzed by IR and NMR spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With Novozyme 435 In acetone at 45 - 60℃; for 0.0208333h; Microwave irradiation; Molecular sieve; Enzymatic reaction; regioselective reaction; | |
94% | With Novozyme 435 In acetone at 45℃; Molecular sieve; Enzymatic reaction; | 2.9.1 Procedure for the synthesis of saturated/unsaturated fatty acid esters of phloridzin and isoquercitrin (2-7 and 9-14) General procedure: To flame dried 3 Å molecular sieves, in round bottom flask, was added phloridzin (0.500 g; 1.15 mmol), stearic acid (1.62 g, 5.72 mmol), Novozyme 435 (1.30 g). It was followed by the addition of dry acetone (5 ml) and the mixture was stirred and heated at 45 °C for 12-24 h. The progress of reaction was monitored by thin layer chromatography (TLC), followed by staining with anisaldehyde spray reagent and then heating at 110 °C. After completion of reaction, it was filtered, evaporated and passed through column chromatography (acetone/toluene; 35:75 to 50:50) to get the pure stearic acid ester (2) of phloridzin. All other reactions followed the same procedure and produced esters 3-7 and 9-14, with yields in the range of 81-98%. The pure compounds were then analyzed by IR, 1H NMR and 13C NMR spectroscopy. All other compounds were prepared by the same method |
91% | With Candida antarctica lipase B In acetone at 40 - 45℃; for 3h; Sonication; Molecular sieve; Enzymatic reaction; regioselective reaction; | 14 General procedure for the biocatalytic esterification reaction ofphloridzin and isoquercitrin (2-11 and 13-21) General procedure: To flame dried 3 Å molecular sieves in an amber color vial, was added phloridzin (0.100 g; 0.23 mmol), butyric acid (0.06 ml,0.69 mmol), Novozyme 435 (0.300 g). It was followed by the addition of dry acetone (5 ml). The reaction was carried out in an ultrasonic bath of 20 kHz/1000W (model 750D, VWR, West Chester, PA, USA) and exposed for 3.5-5 h under ultrasound irradiation alone (for 15-20 min each with 10 min interval in between)and for 2-3.5 h (for 15-20 min each with 10 min interval in between) under ultrasound irradiation coupled with stirring at 40-45 C. The progress of reaction was monitored by thin layer chromatography,followed by staining with anisaldehyde spray reagentand then heating at 110 C. After completion of reaction, it wasfiltered, evaporated and chromatographed (acetone:toluene;35:75-50:50) to get the pure butyric acid ester (2) of phloridzin. All other reactions followed the same procedure and produced esters 2-8 and 9-15, with yields in the range of 81-97%. The pure compounds were then analyzed by IR and NMR spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.0% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; | Reference Example 2 (3R, 4R)-1-Benzylpyrrolidine-3, 4-diyl di ((9Z, 12Z)-octadec-9, 12-dienoate) (compound VI-2) (3R, 4R)-1-Benzylpyrrolidine-3, 4-diol (Diverchim S. A. ; 350 mg, 1.81 mmol) was dissolved in dichloromethane (18 mL). After adding linoleic acid (Aldrich; 1.24 mL, 3.98 mmol), dicyclohexylcarbodiimide (Kokusan Chemical Co., Ltd. ; 860 mg, 4.17 mmol), and 4-dimethylaminopyridine (Tokyo Chemical Industry Co. , Ltd. ; 55.3 mg, 0.453 mmol), the mixture was stirred overnight at room temperature. After adding hexane (18 mL), the reaction mixture was filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/chloroform = 40/60 to 20/80) to give compound VI-2 (1.21 g, 93.0 %). ESI-MS m/z: 719 (M + H)+; 1H-NMR (CDCl3) delta : 0.89 (t, J= 6. 8 Hz, 6H), 1. 30-1. 40 (m, 28H), 1. 55-1. 64 (m, 4H), 2.05 (q, J = 6.6 Hz, 8H), 2. 30 (t, J = 7.5 Hz, 4H), 2. 50 (dd, J = 10.3, 4. 0 Hz, 2H), 2. 77 (t, J = 6.1 Hz, 4H), 3.06 (dd, J = 10.3, 6.1 Hz, 2H), 3. 62 (q, J = 13. 8 Hz, 2H), 5.12 (dd, J = 5.3, 4.0 Hz, 2H), 5. 28-5. 43 (m, 8H), 7. 23-7. 34 (m, 5H). |
93.0% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; | Reference Example 2 (3R,4R)-1-Benzylpyrrolidine-3,4-diyl di((9Z,12Z)-octadec-9,12-dienoate) (compound VI-2) (3R,4R)-1-Benzylpyrrolidine-3,4-diol (Diverchim S. A.; 350 mg, 1.81 mmol) was dissolved in dichloromethane (18 mL). After adding linoleic acid (Aldrich; 1.24 mL, 3.98 mmol), dicyclohexylcarbodiimide (Kokusan Chemical Co., Ltd.; 860 mg, 4.17 mmol), and 4-dimethylaminopyridine (Tokyo Chemical Industry Co., Ltd.; 55.3 mg, 0.453 mmol), the mixture was stirred overnight at room temperature. After adding hexane (18 mL), the reaction mixture was filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/chloroform=40/60 to 20/80) to give compound VI-2 (1.21 g, 93.0%). ESI-MS m/z: 719 (M+H)+; 1H-NMR (CDCl3) delta: 0.89 (t, J=6.8 Hz, 6H), 1.30-1.40 (m, 28H), 1.55-1.64 (m, 4H), 2.05 (q, J=6.6 Hz, 8H), 2.30 (t, J=7.5 Hz, 4H), 2.50 (dd, J=10.3, 4.0 Hz, 2H), 2.77 (t, J=6.1 Hz, 4H), 3.06 (dd, J=10.3, 6.1 Hz, 2H), 3.62 (q, J=13.8 Hz, 2H), 5.12 (dd, J=5.3, 4.0 Hz, 2H), 5.28-5.43 (m, 8H), 7.23-7.34 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid In dichloromethane Reflux; | Synthesis of DCPLA-cyclopropanated oleyl ester Oleyl linoleate was prepared by refluxing linoleic acid (1 g) and oleyl alcohol (1 ml) in CH2CI2 (20 ml) and concentrated H2S04 (10 μΙ) overnight. The product was slightly pink and was purified by flash chromatography. The resultant oleyl linoleate was subjected to the Simmons-Smith procedure described above to generate DCPLA-oleyl ester. | |
With sulfuric acid In dichloromethane Reflux; | Oleyl linoleate was prepared by refluxing linoleic acid (1 g) and oleyl alcohol (1 ml) in CH2CI2 (20 ml) and concentrated H2S04 (10 μΙ) overnight. The product was slightly pink and was purified by flash chromatography. The resultant oleyl linoleate was subjected to the Simmons-Smith procedure described above to generate DCPLA-oleyl ester. | |
With sulfuric acid In dichloromethane | Synthesis of DCPLA-Cyclopropanated Oleyl Ester Oleyl linoleate was prepared by refluxing linoleic acid (1 g) and oleyl alcohol (1 ml) in CH2Cl2 (20 ml) and concentrated H2SO4 (10 μl) overnight. The product was slightly pink and was purified by flash chromatography. The resultant oleyl linoleate was subjected to the Simmons-Smith procedure described above to generate DCPLA-oleyl ester. Synthesis of DCPLA-Retinyl Ester: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: linoleic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2h; Stage #2: benzylamine With dmap In dichloromethane at 20℃; for 18h; | 4.1.1. N-benzylpalmitamide (3a) General procedure: To a solution of palmitic acid (300mg, 1.17mmol) in dichloromethane (DCM, 10mL) was added 1,1′-carbonyldiimdazole (209mg, 1.29mmol). The reaction was stirred at room temperature for 2h. The reaction mixture was slowly added to a solution of benzylamine (153μL, 1.40mmol) and 4-dimethylaminopyridine (14mg, 0.12mmol) in dichloromethane (5mL). The solution was stirred at room temperature for 18h. DCM (100mL) and saturated aqueous NaHCO3 (30mL) were added to the reaction mixture. The organic layer was separated and washed with H2O (30mL), brine (30mL), dried over anhyd sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude was purified by flash chromatography on silica gel eluting with hexane/EtOAc (3:1, v/v) to give the title compound as a white solid (578mg, 86%). Mp 85-87° [lit.45 mp 94.5-95°, and46 fp 95.1°]; 1H NMR (400MHz, CDCl3) δ 7.32-7.36 (m, 2H), 7.26-7.30 (m, 3H), 5.72 (br s, 1H), 4.45 (d, J=6.0Hz, 2H), 2.21 (t, J=7.2Hz, 2H), 1.61-1.67 (m, 2H), 1.25-1.34 (m, 24H), 0.88 (t, J=6.8Hz, 3H); 13C NMR (CDCl3, 100MHz) δ 173.21, 138.66, 128.92, 128.05, 127.71, 43.80, 37.06, 32.16, 29.92, 29.89, 29.84, 29.73, 29.59, 29.56, 26.01, 22.93, 14.36; LCMS, C23H39NO, [M+H]: 346. |
84% | Stage #1: linoleic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.25h; Inert atmosphere; Stage #2: benzylamine In dichloromethane Inert atmosphere; | |
50% | Stage #1: linoleic acid With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.25h; Stage #2: benzylamine With dmap In dichloromethane at 20℃; for 12h; |
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃; | 4 A one-step chemical synthesis of maca amide-N-benzyl-9Z,12Z-octadecenamide 0.010 mol of HOAt, 0.02 mol of EDC · HCl and 0.03 mol of DIPEA were weighed out of 30 mLDCM and 0.01 mol of benzylamine, 0.01 mol of linoleic acid was added and stirred overnight at 25 ° C. 50 mL of deionized water was added at room temperature Stirred for 30 min, filtered and dried in vacuo to give the product; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: linoleic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2h; Stage #2: 3-METHOXYBENZYLAMINE With dmap In dichloromethane at 20℃; for 18h; | 4.1.1. N-benzylpalmitamide (3a) General procedure: To a solution of palmitic acid (300mg, 1.17mmol) in dichloromethane (DCM, 10mL) was added 1,1′-carbonyldiimdazole (209mg, 1.29mmol). The reaction was stirred at room temperature for 2h. The reaction mixture was slowly added to a solution of benzylamine (153μL, 1.40mmol) and 4-dimethylaminopyridine (14mg, 0.12mmol) in dichloromethane (5mL). The solution was stirred at room temperature for 18h. DCM (100mL) and saturated aqueous NaHCO3 (30mL) were added to the reaction mixture. The organic layer was separated and washed with H2O (30mL), brine (30mL), dried over anhyd sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude was purified by flash chromatography on silica gel eluting with hexane/EtOAc (3:1, v/v) to give the title compound as a white solid (578mg, 86%). Mp 85-87° [lit.45 mp 94.5-95°, and46 fp 95.1°]; 1H NMR (400MHz, CDCl3) δ 7.32-7.36 (m, 2H), 7.26-7.30 (m, 3H), 5.72 (br s, 1H), 4.45 (d, J=6.0Hz, 2H), 2.21 (t, J=7.2Hz, 2H), 1.61-1.67 (m, 2H), 1.25-1.34 (m, 24H), 0.88 (t, J=6.8Hz, 3H); 13C NMR (CDCl3, 100MHz) δ 173.21, 138.66, 128.92, 128.05, 127.71, 43.80, 37.06, 32.16, 29.92, 29.89, 29.84, 29.73, 29.59, 29.56, 26.01, 22.93, 14.36; LCMS, C23H39NO, [M+H]: 346. |
39% | Stage #1: linoleic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.25h; Inert atmosphere; Stage #2: 3-METHOXYBENZYLAMINE In dichloromethane Inert atmosphere; | |
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 40℃; for 0.5h; | 5 A one-step chemical synthesis of maca amide-N-(m-methoxybenzyl)-9Ζ,12Z-octadecadienamide 0.02 mol of HOAt, 0.02 mol of EDC · HCl and 0.02 mol of DIPEA were weighed in 30 mL of DCM and 0.01 mol of benzylamine, 0.01 mol of linoleic acid was added and stirred at 40 ° C for 30 min. 50 mL of ion water, stirred at room temperature for 30 min, evaporated to dryness, extracted with chloroform, extracted with nitrogen to the volume without reducing the product.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Intermediate 1: Linoleic acid (50.0 g, 178.30 mmol), N-l3oc-diethanolamine (18.3 g, 89.10 mmol), and DMAP (1.1 g, 8.90 mmol) in an oven-dried flask (1 L) with a magnetic bar was added anhydrous DCM (400 mL). The mixture was stirred at ambient temperature for 2 minutes to a clear solution. EDC (35.9 g, 187.20 mmol) was then added and the mixture was stirred at room temperature overnight (17 hours). The reaction was finally quenched with saturated NaC1 aqueous solution (400 mL) and extracted with DCM twice (400 mL, 100 mL). Organic layers were combined, dried over Na2504 (20 g), and filtered. The filtrate was concentrated under reduced pressure. The crude was dissolved in 50 mL DCM and purified by flash chromatography purification system (330 g silica gel colunm) using a gradient of hexane for 5 mm, then 0-20% EtOAc/hexane for 40 mm under the flow rate at 100 mL/min. The product fractions were collected and concentrated to yield Intermediate 1(59 g, 91% yield) as a clear liquid. ?H mm (400 MHz, CDC13) oe: 5.32-5.33 (8H, m, CH=), 4.13-4.17 (4H, m, OCH2), 3.43-3.49 (4H, m, NCH2), 2.73-2.74 (4H, m, rrrCHCH2CHrrr), 2.03-2.28 (4H, m, CH2CO), 2.00-2.01 (8H, m, =CHCH2), 1.60-1.70 (4H, m, CH2CH2CO), 1.43 (9H, 5, C(CH3)3), 1.28-1.31 (28H, m, CH2), 0.85-0.86 (6H, m, CH3). | |
15.9 g | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;Inert atmosphere; | Step 1: Preparation of Intermediate 1: (9Z,9'Z,12Z,12'Z)-((tert-butoxycarbonyl)azanediyl)bis(ethane-2,1-diyl)bis(octadeca-9,12-dienoate) N-Boc-diethanolamine (5 g, 24.4 mmol), linoleic acid (14.4 g, 51.2 mmol) and was dissolved in DCM (100 mL). EDC HCl salt (10.3 g, 53.7 mmol) was added followed by DMAP (596 mg, 4.88 mmol). The reaction was allowed to stir for about 12 hours at room temperature under a blanket of inert gas. Thereafter, 50 mL of water and 50 mL of methanol were added, and the mixture was stirred for 10 min. The organic layer was isolated and the aqueous layer was further extracted with DCM (150 mL). The combined organics were dried (MgSO4) for 10 min, filtered and concentrated. Purification was by silica gel chromatography, eluating with a hexane/ethyl acetate gradient yielded (9Z,9'Z,12Z,12'Z)-((tert-butoxycarbonyl)azanediyl)bis(ethane-2,1-diyl)bis(octadeca-9,12-dienoate) (15.9 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lipase from Pseudomonas stutzeri PS59 In aq. phosphate buffer; isopropyl alcohol at 30℃; for 0.25h; Enzymatic reaction; | 2.13 Analysis of the substrate specificity of the P. stutzeri PS59 lipase General procedure: An assay mixture consisting of 1 ml of liquid ester or 1 g of solid ester, 3 ml of isopropanol, 5 ml of phosphate buffer (pH=8.0), and 1 ml of the lipase solution was incubated for 15 min at 30°C with stirring at 180 rpm. The reaction was terminated by the addition of 95% ethanol, and the amount of liberated fatty acids after incubation was determined by titrating with 50 mM NaOH in the presence of two drops of phenolphthalein solution as the indicator. The control experiment was performed under the same conditions with the addition of 95% ethanol prior to the reaction. One unit of lipase activity was defined as the amount of enzyme required to liberate 1 μmol of free fatty acid per minute under the experimental conditions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With novozyme 435; In toluene; at 20℃; for 20h;Schlenk technique; Inert atmosphere; Enzymatic reaction; | General procedure: Retinyl esters were synthesized via an enzyme-catalyzed transesterification (19) as follows. Into a dry Schlenk flask, retinyl acetate (33 mg, 0.10 mmol), Novozyme 435 (120 mg), and AberlystA-21 (50 mg) were suspended in dry toluene (5 ml). The reaction mixture was stirred under an atmosphere of N2 , and five equivalents (0.50 mmol) of the appropriate acid (palmitic, stearic, linoleic, or oleic) were added. After 20 h at room temperature, the reaction mixture was filtered and the solvent was removed under reduced pressure to give a mixture (approximately 1:4) of the desired retinyl ester and unreacted acid. The resulting mixtures were used without further purification as LC/MS/MS standards for the corresponding retinyl esters. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.36 g | Intermediate 33a: (9Z,9'Z, 12Z, 12'Z)-(5-(hydroxymethyl)-1 ,3-phenylene)bis(methylene) bis(octadeca-9, 12-dienoate) Linoleic acid (3.42 g, 12.19 mmol) was stirred with EDC (2.33 g, 12.2 mmol) in DCM (30 mL). Once dissolved, DIEA (2.60 mL, 14.9 mmol) and DMAP (145 mg, 1.19 mmol) were added. After 10 minutes stirring, benzene-1 ,3,5-triyltrimethanol (1.0 g, 6.0 mmol) was added and the resulting mixture stirred at room temperature for 3 days. The volatiles were removed under reduced pressure and the resulting crude material was purified on silica using heptanes/EtOAc as eluent, providing 1.36 g of the desired product. TLC (silica gel, 20% EtOAc in heptanes): Rf = 0.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.4% | With tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride; at 50℃; for 72h;Inert atmosphere; | In a typical experiment, 2.7 mg of G2 (3.2 mumol) was dissolved in 10 g of linoleic(35.7 mmol) in a 100 ml glass flask under an N2 atmosphere. The reaction mixture wasstirred and heated at 50C in an oil bath for 72 hours. The reaction mixture wasdissolved in small amount of CHCl3 and precipitated in hexane. The mixture was thenfiltrated and the resulting solid was washed with hexane to give a white powder:Octadec-9-enedioic acid in a 23% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h; | Preparation of Intermediate 1a: (9Z,9'Z, 12Z, 12'Z)-2-(hydroxymethyl)propane- 1 ,3-diyl bis(octadeca-9, 12-dienoate) [0423] In a round bottom flask, linoleic acid (95.0 g, 339 mmol), DMAP (4.14 g, 33.90 mmol), DIPEA (74.1 mL, 424 mmol), and 2-(hydroxymethyl)propane-1 ,3-diol (18.0 g, 170 mmol) were taken into dichloromethane (435 ml). EDC (81 .0 g, 424 mmol) was added in one portion, and the reaction was stirred at ambient temperature. After 24 hours, the reaction is concentrated under reduced pressure with silica gel powder for dry loading and the residue was purified on silica gel (Biotage) using ethyl acetate/heptane (0% to 40%) as eluent, to provide 47 g (44% yield) of the desired product as a colorless oil. [0424] 1H NMR (400 MHz, CDCI3): delta = 5.19-5.50 (m, 8H), 4.19 (tt, J = 1 1.83, 5.87 Hz, 4H), 3.51 -3.69 (m, 2H), 2.78 (t, J = 6.53 Hz, 4H), 2.33 (t, J = 7.53 Hz, 4H), 2.20 (quint, J = 5.83 Hz, 2H), 2.06 (q, J = 6.78 Hz, 8H), 1 .49-1 .72 (m, 5H), 1 .20-1 .46 (m, 26H), 0.79-0.98 (m, 6H) ppm. |
44% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h; | Intermediate 105a: (9Z,9'Z,12Z,12'Z)-2-(hydroxymethyl)propane-1,3-diyl bis(octadeca- 9,12-dienoate) In a round bottom flask, linoleic acid (95.0 g, 339 mmol), DMAP (4.14 g, 33.90 mmol), DIPEA (74.1 ml, 424 mmol), and 2-(hydroxymethyl)propane-1 ,3-diol (18.0 g, 170 mmol) were taken into dichloromethane (435 ml). EDC (81.0 g, 424 mmol) was added in one portion, and the reaction was stirred at ambient temperature. After 24h, the reaction is concentrated under reduced pressure with silica gel powder for dry loading and the residue was purified on silica gel (Biotage) using ethyl acetate /heptane (0% to 40%) as eluent, to provide 47 g (44% yield) of the desired product as a colorless oil. 1H NMR (400 MHz, CDCI3): delta = 5.19-5.50 (m, 8H), 4.19 (tt, J = 1 1.83, 5.87 Hz, 4H), 3.51-3.69 (m, 2H), 2.78 (t, J = 6.53 Hz, 4H), 2.33 (t, J = 7.53 Hz, 4H), 2.20 (quint, J = 5.83 Hz, 2H), 2.06 (q, J = 6.78 Hz, 8H), 1.49-1.72 (m, 5H), 1.20-1.46 (m, 26H), 0.79-0.98 (m, 6H) ppm. |
47 g | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h; | In a round bottom flask, linoleic acid (95.0 g, 339 mmol), DMAP (4.14 g, 33.90 mmol), DIPEA (74.1 ml, 424 mmol), and 2-(hydroxymethyl)propane-1 ,3-diol (18.0 g, 170 mmol) were taken into dichloromethane (435 mL). EDC (81.0 g, 424 mmol) was added in one portion, and the reaction was stirred at ambient temperature. After 24h, the reaction is concentrated under reduced pressure with silica gel powder for dry loading and the residue was purified on silica gel (Biotage) using ethyl acetate /heptane (0% to 40%) as eluent, to provide 47 g of the desired product as a colorless oil. 1H NMR (400 MHz, CDCI3): delta = 5.19-5.50 (m, 8H), 4.19 (tt, J = 1 1.83, 5.87 Hz, 4H), 3.51-3.69 (m, 2H), 2.78 (t, J = 6.53 Hz, 4H), 2.33 (t, J = 7.53 Hz, 4H), 2.20 (quint, J = 5.83 Hz, 2H), 2.06 (q, J = 6.78 Hz, 8H), 1.49-1.72 (m, 5H), 1.20-1.46 (m, 26H), 0.79-0.98 (m, 6H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.5 g; 12.4 g | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h; | Preparation of Intermediate 13c: (9Z,12Z)-3-hydroxy-2-(hydroxymethyl)propyl octadeca-9, 12-dienoate. [0433] In a round bottom flask, linoleic acid (23.78 g, 85 mmol), DMAP (2.072 g, 16.96 mmol), DIPEA (22.22 ml, 127 mmol), and 2-(hydroxymethyl)propane-1 ,3-diol (9 g, 85 mmol) were taken into dichloromethane (200 ml_). EDC (24.39 g, 127 mmol) was added in one portion, and the reaction was stirred at ambient temperature. After 24h, the reaction is concentrated under reduced pressure, and the concentrate is purified on silica gel with ethyl acetate / heptane as eluent to provide 12.4 g of the expected product. 9.5 g of Intermediate 1 a was also isolated. 1H NMR (400 MHz, CDCI3): delta = 4.27 (d, J = 6.27 Hz, 2H), 3.77 (qd, J = 1 1.25, 5.14 Hz, 4H), 2.78 (t, J = 6.40 Hz, 2H), 2.23-2.48 (m, 4H), 1.90-2.15 (m, 6H), 1.53-1.76 (m, 3H), 1.15-1.45 (m, 14H), 0.77-0.98 (m, 3H) ppm. |
9.5 g; 12.4 g | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h; | In a round bottom flask, linoleic acid (23.78 g, 85 mmol), DMAP (2.072 g, 16.96 mmol), DIPEA (22.22 ml, 127 mmol), and 2-(hydroxymethyl)propane-1 ,3-diol (9 g, 85 mmol) were taken into dichloromethane (200 ml_). EDC (24.39 g, 127 mmol) was added in one portion, and the reaction was stirred at ambient temperature. After 24h, the reaction is concentrated under reduced pressure, and the concentrate is purified on silica gel with ethyl acetate / heptane as eluent to provide 12.4 g of the expected product. 9.5 g of Intermediate 1 a was also isolated. 1H NMR (400 MHz, CDCI3): delta = 4.27 (d, J = 6.27 Hz, 2H), 3.77 (qd, J = 1 1.25, 5.14 Hz, 4H), 2.78 (t, J = 6.40 Hz, 2H), 2.23-2.48 (m, 4H), 1.90-2.15 (m, 6H), 1.53-1.76 (m, 3H), 1.15-1.45 (m, 14H), 0.77-0.98 (m, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.5% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 0 - 20℃; for 0.5h;Inert atmosphere; | General procedure: <strong>[62-31-7]Dopamine hydrochloride</strong> (60.7 mg, 0.32 mmol) and palmitoleic acid (91.0 muL, 0.32 mmol) were mixed in dry CH2Cl2(1 mL) under an Ar atmosphere, and triethylamine (133 muL, 0.96 mmol) was added at 0C. PPACA (50% in ethyl acetate, 200 muL, 0.32 mmol) was slowly added over 30 min at the same temperature, and the reaction mixture was stirred at room temperature overnight. The mixture was worked up followed by evaporation, and the residue was purified by column chromatography (eluent; EtOAc-hexane=1 : 1-4 : 1) to give N-palmitoleoyl dopamine (22.6 mg, 18.1%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 14h; | 4.2.2. General experimental procedure for the synthesis of NHPI esters (5a-f) General procedure: The synthesis of NHPI esters (5a-g) followed Qin and coworkers [17] reported procedures with minor modification. Briefly, a round bottom flask (RBF) charged with PUFA (4, 1 eq.), 2- hydroxyisoindoline-1,3-dione (NHPI, 1 eq.), N, N-dimethylpyridin4-amine (DMAP, 0.1 eq.), diisopropylmethanediimine (DIC, 1 eq.) in dry dichloromethane (solvent, PUFA concentration 0.2 M) was stirred at room temperature for 14 h. The resulting mixture was concentrated in vacuo, and the residue was separated over preparative flash chromatography (SiO2, eluted with EtOAc: hexane 6 : 94 to 10 : 90), to yield the desired product as a colorless oil. |
83% | With dmap; dicyclohexyl-carbodiimide In acetonitrile at 22℃; for 18h; | |
79% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 16h; |
78% | With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 4h; | |
77% | With dmap; diisopropyl-carbodiimide In dichloromethane | |
75% | With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 15h; | |
63% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; | |
With dmap; diisopropyl-carbodiimide In dichloromethane | ||
Stage #1: linoleic acid With dmap In dichloromethane at 20℃; for 0.166667h; Stage #2: N-hydroxyphthalimide In dichloromethane at 20℃; | ||
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | ||
With dmap; diisopropyl-carbodiimide at 20℃; | ||
With dmap; diisopropyl-carbodiimide In dichloromethane | ||
With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19 g | [0250] To a solution of linoleic acid (99percent, 49.7 g, 0.177 mol) in 800 mL of anhydrous benzene was added dropwiseoxalyl chloride (99percent, 29.8 g, 0.235 mol) under argon. Upon addition, the resulting mixture was stirred at room temperaturefor 2 hours until no bubble was released. The solvent and excess of oxalyl chloride was removed in vacuo. To the residualwas added anhydrous benzene (1 L) followed by a solution of 3-N,N-dimethylamino-1,2-propanediol and dry pyridinein anhydrous benzene (100 mL) dropwise. The resulting mixture was stirred at room temperature for 2 days. Uponevaporation of the solvent, 64 g of yellowish syrup were afforded. 19 g of pure DLinDAP were obtained upon purificationof the crude product by column chromatography three times on silica gel using 0-5percent methanol gradient in chloroform.1H NMR (400 MHz, CDCl3) delta: 5.49 (1 H, m), 5.43-5.26 (8H, m), 4.41 (1 H, dd), 4.13 (1 H, dd), 3.15-3.35 (2H, m), 2.82(6H, s, 2 x NCH3), 2.76 (4H, t), 2.35-2.6 (2H, m), 2.31 (2H, t), 2.03 (8H, q, vinyl CH2), 1.53-1.68 (4H, m, 2 x CH2), 1.2-1.4(28H, m, 14 x CH2), 0.88 (6H, t, 2 x CH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With platinum on activated charcoal In ethanol; water at 350℃; for 6h; High pressure; Autoclave; | 1 2.3. Reactor and kinetic studies studiesLinoleic acid (>99%, Sigma-Aldrich) and ethanol (99.8%, Sigma-Aldrich) were used as received. The reactions were performed ina 250 mL Hastelloy autoclave (Parr) equipped with high-pressurevalves for liquid or gas introduction and sampling, under autoge-nous pressure. In a typical experiment, the reactor was loaded withwater and the desired amount of catalyst, then purged by bubblingnitrogen in the water for 10 min in order to remove gaseous air anddissolved oxygen. The heating system was then started and sta-bilized at the desired temperature in about 30 min. The mixture oflinoleic acid in ethanol was injected in the autoclave using a prepar-ative HPLC pump. Injection time was set to 2 min. The total liquidvolume loaded in the autoclave was always 150 mL. The stirringrate was set at 300 rpm. In tests performed at 600 rpm the linoleicacid disappearance rate was not modified, showing therefore thatthe reaction was not limited by external mass transfer at 300 rpm.The Weisz-Prater criterion, calculated at 300C using a diffu-sion coefficient of 3.87 10-10m2/s for linoleic acid in water [22],was found <0.05 indicating that internal diffusion limitations werenegligible.Kinetic studies were carried out between 250 and 350C, witha linoleic acid concentration between 1 and 2 g/L and using a cata-lyst/linoleic acid ratio between 0.0625 and 0.125. The initial volumeof solution was always 150 mL. Liquid samples (1 mL) were period-ically collected through a liquid sampling valve and were analyzedby GC-MS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With dicyclohexyl-carbodiimide In methanol; dichloromethane at 35℃; for 0.333333h; Sonication; Flow reactor; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine In dichloromethane at 20℃; for 4h; | Synthesis of Anhydrides General procedure: A 7-ml vial containing aspirin chloride(10 mg, 0.05 mmol) and fatty acid (16 mg, 0.05 mmol for DHA; 15 mg,0.05 mmol and 14 mg, 0.05 mmol for EPA) was dissolved in dichloromethane(DCM; 1 ml, 0.04 M). Pyridine (4 ml, 0.075 mmol) was added to the mixture, and the solution was stirred at room temperature for 4 hours. The reaction was then quenched with 1 ml 1N HCl solution and vortexed. The organic layer was removed and the aqueous layer was re-extracted with 1 ml DCM. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residual solid was recrystallized in diethyl ether to yield a white solid (yields of 3.5 mg, 20% for DHA anhydride; 6 mg, 26% for EPA anhydride; and17.5 mg, 79% for LA anhydride). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 17h; | Intermediate 24: To Fmoc-Dap(l3oc).H20 (10.0 g,22.50 mmol) in an oven-dried flask (250 mE) with a magnetic bar were added anhydrous DCM (100 mE), linoleic acid (7.7 mE, 24.79 mmol), EDC (6.5 g, 33.80 mmol), and DMAP (0.6 g, 4.52 mmol) in sequence. The mixture was stirred at ambient temperature stirred overnight (17 hours). The reaction mixture was concentrated under reduced pressure, dissolved in 5 mE DCM and purified by flash chromatography purification system (220 g silica gel column) using a gradient of 0-50percent EtOAc/hexane for 30 mm under the flow rate at 60 mE/mm. The product fractions were collected and concentrated to yield Intermediate 24 (15.2 g, 100percent yield) as a clear liquid. The product was verified with EC-MS prior to executing the next step?mlz of [M+H] =675.98. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃; | 3 Example 3 Synthesis of CTX Prodrug 3 Containing Unsaturated Alkane Chain Compound To a 100 mL round bottom flask was added CTX (100 mg, 0.12 mmol) and linoleic acid (34 mg, 0.12 mmol)Was dissolved in 5 mL of anhydrous dichloromethane,EDC · HCl (25 mg, 0.13 mmol) was added,4-dimethylaminopyridine (16 mg, 0.13 mmol) and N, N-diisopropylethylamine (21 L, 0.13 mmol).25 ° C overnight,And then with 5% citric acid,Saturated sodium bicarbonate,Saturated brine cleaning;The organic phase was dried over anhydrous sodium sulfate,filter,The filtrate was collected and the solvent was removed under reduced pressure.The solid was purified by column chromatography (DCM: MeOH = 200: 1) to give product 3 (120 mg, yield 91%). |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In water; acetonitrile at 37℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | Specifically, oxalyl chloride (0.72 mL, 8.36 mmol) was added over 10 min to a solution of linoleic acid (2 mL, 6.43 mmol) and DMF (3 drops) in DCM (10 mL) at 0 C, and the solution stirred at room temperature overnight. The solvent and excess oxalyl chloride was removed in vacuo and the residue redissolved in DCM (10 mL). This solution was added dropwise to a solution of <strong>[63069-50-1]3-fluoro-4-aminobenzonitrile</strong> (0.79 g, 5.79 mmol) in DCM (10 mL) and Et3N (1 mL) that had been cooled in an ice bath. Upon complete addition, the solution was stirred at room temperature overnight. The solution was washed with saturated Na2C03 solution (3 chi 20 mL), H20 (20 mL), and brine (20 mL), and dried over MgS04. The resulting residue was subjected to column chromatography, using a gradient elution of EtOAc/petroleum spirits to afford the product as a pale yellow oil that solidified upon cooling. (0597) [00453] Yield: 0.98 g (39%). (0598) [00454] FT- 1 (ATR) Vmait crrr1 : 3328 br w, 2925 m, 2855 m, 2232 w, 1709 m, 1616 m, 1594 m, 1517 s. 1 H-NMR delta/ppm (d6-DMSO): 10.07 (1 H, s, NH) , 8.32 (1 H, m, Ar CH), 7.91 (1 H, dd, 3JH,F = 1 1 .1 Hz, 4JH,H = 1 .9 Hz, Ar CH), 7.68 (1 H, ddd, 3JH,H = 8.6 Hz, 4JH,H = 1 .9 Hz, 5JH,F = 0.9 Hz Ar CH), 5.28 - 5.43 (4 chi 1 H, 4 chi m, 4 chi olefinic CH), 2.77 (2H, m, CH2), 2.48 (2H, m, NHCOCH2), 2.00 - 2.10 (2 x 2H, 2 x m, 2 x CH2), 1 .61 (2H, m, CH2), 1 .24 - 1 .40 (7 chi 2H, 7 chi m, 7 chi CH2), 0.88 (3H, m, CH3). 13C-NMR delta/ppm (d6-DMSO): 172.4 (CONH), 151 .7 (d, 1 JC,F = 247 Hz, Ar CF), 131 .6 (d, 2JC,F = 1 1 .2 Hz, Ar C), 129.70 (olefinic CH), 129.68 (olefinic CH), 129.3 (d, 3JC,F = 3.5 Hz, Ar CH), 127.74 (olefinic CH), 127.71 (olefinic CH), 122.9 (d, 4JC,F = 2.9 Hz, Ar CH), 1 19.3 (d, 2JC,F = 23.4 Hz, Ar CH), 105.7 (d, 3JC,F = 9.3 Hz, Ar C), 1 17.9 (d, 3JC,F = 2.7 Hz, CN), 35.9 (NHCOCHs), 30.9 (CH2), 29.0 (CH2), 28.7 (CH2), 28.6 (CH2), 28.52 (CH2), 28.5 (CH2), 26.6 (CH2), (0599) 25.2 (CH2), 24.9 (CH2), 21 .9 (CH2), 13.9 (CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With dmap; dicyclohexyl-carbodiimide; In chloroform; at 20℃; for 120h; | Intermediate 2 (300 mg, 0.57 mmol) was dissolved in CHCh (10 mL), then fatty acid (1.15 mmol), 4-DMAP (140 mg, 1.15 mmol) and DCC (236 mg, 1.15 mmol) were added. The reaction mixture was stirred at 20 C for 5 days, the solids were filtered and washed with CHCh. The solvent was evaporated and the residue was chromatographed on silica in CHCh, CHCh- MeOH (2: 1, 1 : 1, 1 :2) and MeOH. The pure fractions were evaporated to give product as a colorless waxy substance. Rf 0.40 (CHCh, MeOH, cone. M 13 :5: 1). (0237) [0160] l-Acyl-2-linoleyl-sn-glycero-3-phosphatidylcholine (3a). Yield 344 mg (77%). NMR (CDCh) d 5.36 (m, 4H), 4.41 (m, 1H), 4.30 (m, 2H), 4.11 (dd, J= 12.1, 7.4 Hz, (0238) 1H), 4.00-3.85 (m, 2H), 3,76 (m, 2H), 3.33 (m, 9H), 2.80 (m, 2H), 2.28 (m, 4H), 2.10 (m, 4H), 1.58 (m, 4H), 1.24 (m, 40H), 0.97 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Add appropriate amount of ethylene glycol to 50mL three-necked flask, add a small amount of p-toluenesulfonic acid, heat to 110 C, slowly dissolve the oleic acid dissolved in toluene into the reaction bottle, react for 2h, and monitor the reaction process by thin layer chromatography. Then, 20 mL of toluene was added to the system three times, and distilled under reduced pressure. The obtained product was dissolved in 30 mL of dichloromethane, and an appropriate amount of thiodiacetic anhydride and a small amount of triethylamine, HOBT, EDCI were added, and the mixture was stirred at room temperature for 24 hours.The reaction was monitored by thin layer chromatography and purified by silica gel column chromatography. Finally, the intermediate product, EDCI, HOBt and DMAP were dissolved in 50 mL of anhydrousIn dichloromethane, ice bath for 2 hours, then add appropriate amount of paclitaxel, stir at room temperature for another 48 hours, and monitor the reaction by thin layer chromatography.The target product is obtained by preparative liquid chromatography separation and purification. The above reaction was carried out under the protection of N2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.4% | With Candida antarctica lipase B immobilized on resin beads; In acetone; at 50℃; for 96h;Enzymatic reaction; | General procedure: Synthesis was carried out following a previously reported method (Vaisali et al., 2017) with some modifications. Esterification of palmitic acid and <strong>[27208-80-6]polydatin</strong> was used to standardise reaction conditions for other fatty acids. Reactions were performed in a 30 mL hermetically sealed bottle consisting of previously dried <strong>[27208-80-6]polydatin</strong> (0.2 mmol, 78 mg), palmitic acid (0.8 mmol, 205 mg), 5 mL solvent and 75 mg Novozym 435. The reaction mixture was kept in an orbital shaker at constant agitation of 150 rpm and 50 C for 6 days. Samples were analysed using HPLC and LCMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: linoleic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: hydroxytyrosol With dmap In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; | 1 Connect a magnetic stirrer and a three-necked flask (with a rubber stopper) as a reaction device, place the reaction device in an ice bath environment, and pass nitrogen to obtain 0, N2The experimental conditions.0.8 g of linoleic acid and 0.6 g of EDC were added to 20.0 mL of dry tetrahydrofuran (THF), and magnetically stirred for 0.5 h.Then add dropwise the mixed solution (0.5g hydroxytyrosol and 0.1g DMAP dissolved in 10.0mL dry THF).Remove the ice bath device, allow the temperature to gradually return to room temperature, continue the reaction for 24 hours, after the reaction is over, pour the mixture into saturated NaHCO3Wash the solution, then extract 3 times with 30.0 mL of dichloromethane, separate the organic phase, and use Na2SO4Dry and concentrate by rotary evaporation at 25 rpm/min below 50°C to obtain the crude reactant.The crude reactant was separated and purified by silica gel chromatography (mobile phase was a mixture of dichloromethane and methanol).The chemical structure of the purified substance was identifiedby1H-NMR, and the molecular weight of the purified substance was verified by ESI-MS. From this, the synthesized substance was judged to be the target compound.1H-NMR is shown in Figure 2 and ESI-MS is shown in Figure 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: linoleic acid With dicyclohexyl-carbodiimide In dichloromethane for 0.25h; Cooling with ice; Inert atmosphere; Stage #2: methyl ricinoleate With dmap In dichloromethane at 20℃; for 16h; Cooling with ice; Inert atmosphere; | 1 General Procedure B - Acylation of Hydroxy Fatty Acid Esters General procedure: N,N'-Dicyclohexylcarbodiimide (DCC; 1.00 equiv. per hydroxyl + additional 0.10 equiv.) was added to an ice-cold CH2Cl2 (0.3 M) solution of the desired carboxylic acid (1.00 equiv. per hydroxyl + additional 0.10 equiv.) in a round bottom flask under argon. Subsequently, the ice bath was removed and the resultant mixture stirred for 15 min. The reaction mixture was cooled again in an ice bath and solid hydroxy fatty acid (1.00 equiv.) was added thereto, followed by the addition of 4-dimethylaminopyridine (DMAP; 1.00 equiv. per hydroxyl + additional 0.50 equiv.). The reaction mixture was allowed to warm to room temperature over 16 h, then diluted with hexanes, stirred for 10 min and subsequently filtered through a pad of Celite. The filtrate was concentrated on a rotary evaporator to yield a crude mixture from which the desired acylated material was purified by flash column chromatography. According to General Procedure B, methyl ricinoleate (500 mg, 1.60 mmol), linoleic acid (538 mg, 1.92 mmol, 1.20 equiv.), DCC (396 mg, 1.20 mmol, 2.20 equiv.) and DMAP (293 mg, 2.40 mmol, 1.50 equiv.) in CH2Cl2 (5 mL) afforded the title compound (875 mg, 93% yield) as a clear, colourless oil. 1H (300 MHz, CDCl3): 5.55-5.28 (m, 6H), 4.90 (quint, J = 6.2 Hz, 1H), 3.69 (s, 3H), 2.79 (t, J = 5.8 Hz, 2H), 2.40-2.21 (m, 6H), 2.16-1.93 (m, 6H), 1.72-1.46 (m, 8H), 1.46-1.18 (m, 32H), 1.00-0.80 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With Novozyme 435 immobilized on acrylic resin In hexane at 40℃; | 2.1.1 Synthesis and purification of LEA and LEA-d4 General procedure: For the synthesis of LEA, we followed a previously documented strategy involving the enzyme Novozym 435 [25]. In brief, we mixed LA and ethanolamine (0.20mmol of each) in a glass vial containing 1ml hexane. The resulting mixture was placed in a thermoconstant girotory shaker (New Brunswick Scientific, USA) and 50mg of Novozym 435 was then added. The mixture was shaken at 200rpm overnight at 40°C. After cooling at room temperature, removal of the solvents was performed under reduced pressure. Purification of LEA was achieved by silica gel chromatography using CHCl3-MeOH (98:2, v/v) to give 54mg (0.17mmol) of LEA (1) (white solid, 85% yield). For the synthesis of LEA-d4, we essentially performed the same steps, but we replaced ethanolamine with ethanolamine-d4. This led to the synthesis of LEA-d4 (2) in good yield (white solid, 85% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.46% | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 25℃; for 18h; | 1 [Example 1] Synthesis of Glycerol Derivative (EC-A04_2) 2-Amino propane-1,3-diol (1.5 eq.) as starting material, Triethylamine (TEA, 6 eq.), linoleic acid (2 g, 7.13 mmole, 1 eq.), HOBt (1-Hydroxybenzotriazole, 1.2 eq.) and EDCI (N-(3-Dimethylamino propyl)-N′-ethylcarbodiimide, 1.2 eq.) were added to 500 ml of MC (Methylene chloride), and stirred at 25° C. for 18 hours. The solvent was concentrated and purified by column (MC:MeOH=100:1→10:1) to obtain the target compound 1 (L=linoleoyl, MeOH=methanol, yield 90.46%). |
90.46% | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 25℃; for 18h; | 5.5a; 7 2-Amino propane-1,3-diol, 1.5eq TEA, linoleic acid, 2g, 7.13mmole, 1eq. ), HOBt (1- Hydroxybenzotriazole, 1.2eq.) and EDCI (N -3 Dimethylamino propyl)-(N- ethylcarbodiimide, 1.2eq.), as a starting material, were combined in 500 ml of MC and stirred at 25 C for 18 hours. The reaction solution was concentrated and purified by column (gradient eluent MC: MeOH from 100: 1 to 10: 1) to obtain the compound 1 (L = Linoleoyl). (MeOH = methanol, Yield 90.46%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 17h; Inert atmosphere; | 3-((tert-Butoxy(2-((tert-butoxycarbonyl)amino)ethoxy)phosphoryl)oxy)propane-1,2-diyl (9Z,9′Z,12Z,12′Z)-Bis(octadeca-9,12-dienoate)(8ab) To solution of diol 7a (210 mg, 0.6 mmol), linoleic acid (633 mg, 2.3 mmol) and DMAP (70 mg, 0.6 mmol) in CH2Cl2 (6.0 mL) was added EDC·HCl (328 mg, 1.7 mmol) at room temperature. After stirring for 17 h at room temperature under N2, the reaction mixture was diluted with EtOAc and then washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc, 3:2) to give the target product 8ab as a diastereomeric mixture (412 mg, 81%, colorless oil). IR (ATR): 2924, 2854, 1741, 1715, 1514, 1458, 1365, 1250, 1170, 1038,1001, 863, 777 cm-1. 1H NMR (500 MHz, CDCl3): = 5.41-5.30 (m, 8 H), 5.25-5.22 (m, 1 H),5.13 (br, 1 H), 4.35 (ddd, J = 11.9, 4.2, 1.4 Hz, 1 H), 4.18-4.09 (m, 3 H),4.09-4.03 (m, 2 H), 3.40 (d, J = 4.4 Hz, 2 H), 2.77 (t, J = 6.6 Hz, 4 H),2.33 (t, J = 7.9 Hz, 2 H), 2.31 (t, J = 7.8 Hz, 2 H), 2.05 (q, J = 6.8 Hz, 8 H),1.62-1.59 (m, 4 H), 1.505 (s, 9 H, A), 1.499 (s, 9 H, B), 1.44 (s, 9 H),1.37-1.25 (m, 28 H), 0.89 (t, J = 6.9 Hz, 6 H). 13C NMR (126 MHz, CDCl3): = 173.2, 172.8, 155.7, 130.2, 130.0,128.0, 127.8, 84.02 (d, J = 7.7 Hz, A), 83.96 (d, J = 7.6 Hz, B), 79.4, 69.4(d, J = 8.1 Hz), 66.8 (d, J = 6.2 Hz), 64.9 (d, J = 5.5 Hz), 61.7, 40.9 (d, J =6.0 Hz), 34.1, 34.0, 31.9, 31.54, 31.48, 29.75, 29.71, 29.6, 29.3, 29.2,29.08, 29.05, 29.02, 28.3, 27.2, 25.6, 24.8, 22.5, 14.0. 31P NMR (202 MHz, CDCl3): = -4.77 (A), -4.84 (B). MS (ESI): m/z = 919 [M + Na]+. HRMS (ESI): m/z [M + Na]+ calcd for C50H90NNaO10P: 918.6200; found: 918.6217. |
Tags: 60-33-3 synthesis path| 60-33-3 SDS| 60-33-3 COA| 60-33-3 purity| 60-33-3 application| 60-33-3 NMR| 60-33-3 COA| 60-33-3 structure
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P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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