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Linoleyl Methane Sulfonate is a lipid.
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| CAS No. : | 51154-39-3 |
| Formula : | C19H36O3S |
| M.W : | 344.55 |
| SMILES Code : | CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O |
| MDL No. : | MFCD00674729 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H302-H315-H319 |
| Precautionary Statements: | P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330 |
* 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 |
|---|---|---|
| 60% | Synthesis of 1, 2-DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA) and 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA) (0249) 3-(Dimethylamino)-1,2-propanediol (714 mg, 6 mmol) and 95% sodium hydride (NaH, 1.26 g, 50 mmol) are stirred in benzene (30 mL) under nitrogen for 30 minutes. Linoleyl mesylate (5.0 g, 15 mmol) is added and the reaction refluxed under nitrogen for 3 hours. The reaction mixture is then cooled in an ice bath while quenching via the slow addition of ethanol. Following dilution with a further 150 mL of benzene, the mixture is washed with distilled water (2×150 mL) and brine (150 mL). The organic phase is dried over magnesium sulphate and evaporated to give the crude product. (0250) The crude product is purified on a silica gel (Kiesel Gel 60) column eluted with 0-5% methanol in chloroform. Column fractions are analyzed by thin layer chromatography (TLC) (silica gel, chloroform/methanol 9:1 v/v, visualized with molybdate dip) and fractions containing purified product (Rf=0.5) are pooled and concentrated. (0251) Decolorization and further purification of DLinDMA is effected with a second column, this time eluting with 20-50% ethyl acetate in hexane. Column fractions are analyzed by TLC (silica gel, ethyl acetate/hexane 1:1 v/v, visualized with molybdate) and fractions containing pure product (Rf=0.4) are pooled and concentrated. The procedure described herein typically yields 2.2 g (60%) of pure product. | |
| EXAMPLE 2SYNTHESIS OF 1 ,2-DILINOLEYLOXY-N1N-DIMETHYL-S-AMINOPROPANE (DLINDMA) DLinDMA was synthesized as described below.1 ,2-Dilinoleyloxy-3-dimethylaminopropane (DLinDMA)To a suspension of NaH (95%, 5.2 g, 0.206 mol) in 120 mL of anhydrous benzene was added dropwise N,N-dimethyl-3-aminopropane-1 ,2- diol (2.8 g, 0.0235 mol) in 40 mL of anhydrous benzene under argon. Upon addition, the resulting mixture was stirred at room temperature for 15 min. Linoleyl methane sulfonate (99%, 20 g, 0.058 mol) in 75 mL of anhydrous benzene was added dropwise at room temperature under argon to the above mixture. After stirred at room temperature for 30 min., the mixture was refluxed overnight under argon. Upon cooling, the resulting suspension was treated dropwise with 250 ml_ of 1 :1 (V:V) ethanol-benzene solution. The organic phase was washed with water (150 ml_), brine (2 x 200 ml_), and dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo to afford 17.9 g of light oil as a crude product. 10.4 g of pure DLinDMA were obtained upon purification of the crude product by column chromatography twice on silica gel using 0-5% methanol gradient in methylene chloride. 1 H NMR (400 MHz, CDCI3) delta: 5.35 (8H, m, CH=CH), 3.5 (7H, m, OCH), 2.75 (4H, t, 2 x CH2), 2.42 (2H, m, NCH2), 2.28 (6H, s, 2 x NCH3), 2.05 (8H, q, vinyl CH2), 1.56 (4H, m, 2 x CH2), 1.28 (32H, m, 16 x CH2), 0.88 (6H, t, 2 x CH3) ppm. | ||
| To a suspension of NaH (95%, 5.2 g, 0.206 mol) in 120 mL of anhydrous benzene was added dropwise N,N-dimethyl-3-aminopropane-1,2-diol (2.8 g, 0.0235 mol) in 40 mL of anhydrous benzene under argon. Upon addition, the resulting mixture was stirred at room temperature for 15 min. Linoleyl methane sulfonate (99%, 20 g, 0.058 mol) in 75 mL of anhydrous benzene was added dropwise at room temperature under argon to the above mixture. After stirred at room temperature for 30 min., the mixture was refluxed overnight under argon. Upon cooling, the resulting suspension was treated dropwise with 250 mL of 1:1 (V:V) ethanol-benzene solution. The organic phase was washed with water (150 mL), brine (2×200 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo to afford 17.9 g of light oil as a crude product. 10.4 g of pure DLinDMA were obtained upon purification of the crude product by column chromatography twice on silica gel using 0-5% methanol gradient in methylene chloride. 1H NMR (400 MHz, CDCl3) delta: 5.35 (8H, m, CHCH), 3.5 (7H, m, OCH), 2.75 (4H, t, 2×CH2), 2.42 (2H, m, NCH2), 2.28 (6H, s, 2×NCH3), 2.05 (8H, q, vinyl CH2), 1.56 (4H, m, 2×CH2), 1.28 (32H, m, 16×CH2), 0.88 (6H, t, 2×CH3) ppm |
| 10.4 g | [0211] To a suspension of NaH (95%, 5.2 g, 0.206 mol) in 120 mL of anhydrous benzene was added dropwise N,Ndimethyl-3-aminopropane-1,2-diol (2.8 g, 0.0235 mol) in 40 mL of anhydrous benzene under argon. Upon addition, theresulting mixture was stirred at room temperature for 15 min. Linoleyl methane sulfonate (99%, 20 g, 0.058 mol) in 75mL of anhydrous benzene was added dropwise at room temperature under argon to the above mixture. After stirred atroom temperature for 30 min., the mixture was refluxed overnight under argon. Upon cooling, the resulting suspensionwas treated dropwise with 250 mL of 1:1 (V:V) ethanol-benzene solution. The organic phase was washed with water(150 mL), brine (2 x 200 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo to afford 17.9g of light oil as a crude product. 10.4 g of pure DLinDMA were obtained upon purification of the crude product by columnchromatography twice on silica gel using 0-5% methanol gradient in methylene chloride. 1 H NMR (400 MHz, CDCl3)delta: 5.35 (8H, m, CH=CH), 3.5 (7H, m, OCH), 2.75 (4H, t, 2 x CH2), 2.42 (2H, m, NCH2), 2.28 (6H, s, 2 x NCH3), 2.05 (8H,q, vinyl CH2), 1.56 (4H, m, 2 x CH2), 1.28 (32H, m, 16 x CH2), 0.88 (6H, t, 2 x CH3) ppm. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| ~ 100% | With magnesium bromide ethyl etherate; In diethyl ether; for 21h;Inert atmosphere; | Synthesis of Linoleyl Bromide (II)A mixture of linoleyl methane sulfonate (6.2g, 18 mmol) and magnesium bromide etherate (17g, 55 mmol) in anhydrous ether (300 mL) was stirred under argon overnight (21 hours). The resulting suspension was poured into 300 mL of chilled water. Upon shaking, the organic phase was separated. The aqueous phase was extracted with ether (2 x 150 mL). The combined ether phase was washed with water (2 x 150 mL), brine (150 mL), and dried over anhydrous Na2SO4. The solvent was evaporated to afford 6.5g of colourless oil. The crude product was purified by column chromatography on silica gel (230- 400 mesh, 300 mL) and eluted with hexanes. This gave 6.2 g (approximately 100%) of linoleyl bromide (II). 1 H NMR (400 MHz, CDCI3) delta: 5.27-5.45 (4H, m, 2 x CH=CH), 3.42 (2H, t, CH2Br), 2.79 (2H, t, C=C-CH2-C=C), 2.06 (4H, q, 2 x allylic CH2), 1.87 (2H, quintet, CH2), 1.2-1.5 (16H, m), 0.90 (3H, t, CH3) ppm. |
| 100% | With magnesium bromide ethyl etherate; In diethyl ether; for 21h;Inert atmosphere; | A mixture of linoleyl methane sulfonate (6.2 g, 18 mmol) and magnesium bromide etherate (17 g, 55 mmol) in anhydrous ether (300 mL) was stirred under argon overnight (21 hours). The resulting suspension was poured into 300 mL of chilled water. Upon shaking, the organic phase was separated. The aqueous phase was extracted with ether (2×150 mL). The combined ether phase was washed with water (2×150 mL), brine (150 mL), and dried over anhydrous Na2SO4. The solvent was evaporated to afford 6.5 g of colourless oil. The crude product was purified by column chromatography on silica gel (230-400 mesh, 300 mL) eluted with hexanes. This gave 6.2 g (approximately 100%) of linoleyl bromide (II). 1H NMR (400 MHz, CDCl3) : 5.27-5.45 (4H, m, 2×CHCH), 3.42 (2H, t, CH2Br), 2.79 (2H, t, CC-CH2-CC), 2.06 (4H, q, 2×allylic CH2), 1.87 (2H, quintet, CH2), 1.2-1.5 (16H, m), 0.90 (3H, t, CH3) ppm. |
| 100% | With magnesium bromide; In diethyl ether; for 21h;Inert atmosphere; | [0204] A mixture of linoleyl methane sulfonate (6.2g, 18 mmol) and magnesium bromide etherate (17g, 55 mmol) inanhydrous ether (300 mL) was stirred under argon overnight (21 hours). The resulting suspension was poured into 300mL of chilled water. Upon shaking, the organic phase was separated. The aqueous phase was extracted with ether (2x 150 mL). The combined ether phase was washed with water (2 x 150 mL), brine (150 mL), and dried over anhydrous Na2SO4. The solvent was evaporated to afford 6.5g of colourless oil. The crude product was purified by column chromatographyon silica gel (230-400 mesh, 300 mL) eluted with hexanes. This gave 6.2 g (approximately 100%) of linoleylbromide (II). 1 H NMR (400 MHz, CDCl3) delta: 5.27-5.45 (4H, m, 2 x CH=CH), 3.42 (2H, t, CH2Br), 2.79 (2H, t, C=CCH2-C=C), 2.06 (4H, q, 2 x allylic CH2), 1.87 (2H, quintet, CH2), 1.2-1.5 (16H, m), 0.90 (3H, t, CH3) ppm. |
| 99% | With magnesiumbromide etherate; In diethyl ether;Inert atmosphere; | Magnesium bromide etherate (34 g, 1 10 mmol) and a stir bar were added to a 2000 mL round bottom flask. The flask was sealed and flushed with nitrogen.Anhydrous diethyl ether (400 mL) was added via canulla. A solution of linolenyl mesylate (20 g, 58 mmol) in anhydrous ether (300 mL) was then added, and the suspension stirred overnight. The suspension was poured into 500 mL of chilled water and transferred to a 2000-mL separating funnel. After shaking, the organic phase was separated. The aqueous phase was then extracted with ether (2 x 250 mL) and all ether phases combined. The ether phase was washed with water (2 x 250 mL), brine (250 mL) and dried over anhydrousMg2S04. The solution was filtered, concentrated and purified by flash chromatography. Final yield 18.9 g, 99%. |
| 99% | With magnesium bromide ethyl etherate; In diethyl ether;Inert atmosphere; Sealed tube; | General procedure: Step 1: Magnesium bromide etherate (34 g, 110 mmol) and a stir bar were added to a 2000 mL round bottom flask. The flask was sealed and flushed with nitrogen. Anhydrous diethyl ether (400 mL) was added via canulla. A solution of linolenyl mesylate (20 g, 58 mmol) in anhydrous ether (300 mL) was then added, and the suspension stirred overnight. The suspension was poured into 500 mL of chilled water and transferred to a 2000-mL separating funnel. After shaking, the organic phase was separated. The aqueous phase was then extracted with ether (2×250 mL) and all ether phases combined. The ether phase was washed with water (2×250 mL), brine (250 mL) and dried over anhydrous Mg2SO4. The solution was filtered, concentrated and purified by flash chromatography. Final yield 18.9 g, 99%. |
| 99% | With magnesium bromide diethyl etherate; In diethyl ether;Sealed tube; Inert atmosphere; | STEP 1: Magnesium bromide etherate (34 g, 110 mmol) and a stir bar were added to a 2000 mE round bottom flask. The flask was sealed and flushed with nitrogen. Anhydrous diethyl ether (400 mE) was added via canulla. A solution of linolenyl mesylate (20 g, 58 mmol) in anhydrous ether (300 mE) was then added, and the suspension stirred overnight. The suspension was poured into 500 mE of chilled water and transferred to a 2000-mE separating flannel. After shaking, the organic phase was separated. The aqueous phase was then extracted with ether (2x250 mE) and all ether phases combined. The ether phase was washed with water (2x250 mE), brine (250 mE) and dried over anhydrous Mg2SO4. The solution was filtered, concentrated and purified by flash chromatography. Final yield 18.9 g, 99%. |
| 97% | With lithium bromide; In diethyl ether; at 20℃; for 24h;Inert atmosphere; | Linoleyl methanesulfonate (27 g, 78 mmoles), anhydrous magnesium bromide (43 g; 238 mmoles), and 1000 ml of dry ether was placed in a 2500 ml three-necked flask equipped with reflux condenser, inlet and outlet tubes for dry nitrogen, and mechanical stirrer. The mixture was stirred vigorously at room temperature for 24 hr. More ether, and cold, degassed water were added after 24 hours. The water layer was extracted twice with ether. The combined ether phases were washed consecutively with water, 1% potassium carbonate solution, and water, and are dried over anhydrous sodium sulfate. Concentration of the ether phase using a rotary evaporator yielded 25 g (97%) of linoleyl bromide; mp -35 C. |
| 94% | With magnesium bromide ethyl etherate; In diethyl ether; for 26h;Inert atmosphere; Reflux; | Synthesis of 18-Bromo-octadeca-6,9-diene 3 The mesylate 2 (13.44 g, 39 mmol) was dissolved in anhydrous ether (500 mL) and to it the MgBr.Et2O complex (30.7 g, 118 mmol) was added under argon and the mixture was refluxed under argon for 26 h after which the TLC showed the completion of the reaction. The reaction mixture was diluted with ether (200 mL) and ice-cold water (200 mL) was added to this mixture and the layers were separated. The organic layer was washed with 1% aqueous K2CO3 (100 mL), brine (100 mL) and dried (Anhyd. Na2SO4). Concentration of the organic layer provided the crude product which was further purified by column chromatography (silica gel) using 0-1% Et2O in hexanes to isolate the bromide 3 (12.6 g, 94%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) delta=5.41-5.29 (m, 4H), 4.20 (d, 2H), 3.40 (t, J=7 Hz, 2H), 2.77 (t, J=6.6 Hz, 2H), 2.09-2.02 (m, 4H), 1.88-1.00 (m, 2H), 1.46-1.27 (m, 18H), 0.88 (t, J=3.9 Hz, 3H). 13C NMR (CDCl3) delta=130.41, 130.25, 128.26, 128.12, 34.17, 33.05, 31.75, 29.82, 29.57, 29.54, 29.39, 28.95, 28.38, 27.42, 27.40, 25.84, 22.79, 14.28. |
| 94% | With magnesium bromide ethyl etherate; In diethyl ether; for 26h;Inert atmosphere; Reflux; | The mesylate (2) (13.44 g, 39 mmol) was dissolved in anhydrous ether (500 mL) and to it the MgBr.Et2O complex (30.7 g, 118 mmol) was added under argon and the mixture was refluxed under argon for 26 h after which the TLC showed the completion of the reaction. The reaction mixture was diluted with ether (200 mL) and ice-cold 12 water (200 mL) was added to this mixture and the layers were separated. The organic layer was washed with 1% aqueous K2CO3 (100 mL), brine (100 mL) and dried (Anhyd. Na2SO4). Concentration of the organic layer provided the crude product which was further purified by column chromatography (silica gel) using 0-1% 9 Et2O in hexanes to isolate the bromide 3 (12.6 g, 94%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) delta=5.41-5.29 (m, 4H), 4.20 (d, 2H), 3.40 (t, J=7 Hz, 2H), 2.77 (t, J=6.6 Hz, 2H), 2.09-2.02 (m, 4H), 1.88-1.00 (m, 2H), 1.46-1.27 (m, 18H), 0.88 (t, J=3.9 Hz, 3H). 13C NMR (CDCl3) delta=130.41, 130.25, 128.26, 128.12, 34.17, 33.05, 31.75, 29.82, 29.57, 29.54, 29.39, 28.95, 28.38, 27.42, 27.40, 25.84, 22.79, 14.28. |
| 93% | With magnesium bromide ethyl etherate; In diethyl ether; at 20℃; for 16h; | Step 2: (6Z,9Z)-18-Bro (3066) Chemical Formula: Ci8H33Br (3067) Molecular Weight: 329.37 (3068) [00836] To a solution of (9Z, 12Z)-octadeca-9, 12-dien-l-yl methanesulfonate (10.0 g, 29.0 mmol) in diethyl ether (372 mL) was added magnesium bromide ethyl etherate (22.5 g, 87.1 mmol). The reaction was let stir at room temperature for 16 hours. The mixture was quenched by the addition of water and extracted with diethyl ether. The combined organic layers were washed with 1% K2CO3, brine, dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. Purification by ISCO silica flash chromatography provided (6Z,9Z)-18-bromooctadeca- 6,9-diene (8.9 g, 93%). ^-NMR (300 MHz, CDC13) delta: ppm 5.36 (m, 4H); 3.41 (t, 2H); 2.77 (t, 2H); 2.05 (q, 4H); 1.86 (m, 2H); 1.48-1.22 (br. m, 16H); 0.89 (t, 3H). |
| 92% | With magnesium bromide ethyl etherate; In diethyl ether; at 20℃; for 2h;Inert atmosphere; | To a solution of linoleyl methanesulfonate (26 g, 75 mmol) in ether (800 mL) was added magnesium bromide ethyl etherate (58.5 g, 226 mmol) under Argon. The reaction mixture was stirred at room temperature for 2 hrs. TLC was used to monitor reaction progress. If not completed, additional magnesium bromide ethyl etherate (14.5 g) was added the reaction mixture and the reaction mixture was stirred at room temperature for 22 hrs. TLC showed the reaction was complete (9/1 hexane/EtOAc). The reaction mixture was filtered, washed with ether (200 mL), hexane (100 mL), and concentrated under reduced pressure to give a residue, which was purified by ISCO (200 g gold silica gel cartridge) eluted with hexane to 10% EtOAc in hexane to give linoleyl bromide (22.8 g, 69.2 mmol, 92 % yield) as a colorless oil. 1H NMR (500 MHz, Chloroform-d) delta 5.42- 5.31 (m, 4H), 3.41 (t, J = 6.9 Hz, 2H), 2.77 (t, J = 6.6 Hz, 2H), 2.05 (q, J = 6.9 Hz, 4H), 1.85 (p, J = 6.9 Hz, 2H), 1.43- 1.25 (m, 16H), 0.89 (t, J = 6.8 Hz, 3H). |
| 87% | With magnesium bromide ethyl etherate; In diethyl ether; at 20℃; | (9z,12z)-Octadecadien-1-methanesulfonate (10.64 g) was dissolved in diethyl ether (140 mL), magnesium bromide ethyl etherate (16.0 g, 61.8 mmol) was added to the solution, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was collected, and washed by using saturated aqueous sodium hydrogencarbonate (100 mL). Then, anhydrous sodium sulfate was added to the organic layer for dehydration. 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 18-bromo-octadeca-(6z,9z)-diene (8.85 g, 26.9 mmol) as colorless oil. Yield was 87%. Proton nuclear magnetic resonance (1H NMR, 500 MHz) data of 18-bromo-octadeca-(6z,9z)-diene delta=0.88 (t, 3H), 1.27-1.46 (m, 18H), 1.80-1.88 (m, 2H), 2.00-2.09 (m, 4H), 2.77 (t, 2H), 3.40 (t, 2H), 4.20 (d, 2H), 5.29-5.41 (m, 4H) |
| 81% | With lithium bromide; In N,N-dimethyl-formamide; at -10 - 0℃; for 1.5h;Inert atmosphere; Large scale; | A clean dry 200 L total glass reactor fitted with an argon inlet and a thermowell was charged with 25 L of DMF and 7.1 Kg of crude product from step 2. The mixture was cooled to -10 C. using an acetone-dry ice mixture. To this stirred mixture was added 25 L of a DMF solution of lithium bromide (2.7 Kg, 31.0 mol) over 1.5 hours while maintaining the reaction temperature below 0 C. After the addition was complete, the reaction mixture was stirred at 45 C. for 18-20 hours until TLC of the aliquot (10% EtOAc in hexane, PMA staining) showed complete disappearance of the starting mesylate. The reaction mixture was diluted with 70 L of water and extracted with 57 L of hexane. The aqueous layer was further extracted with 2 × 10 L of hexane and the combined organic layers (~ 120 L was washed again with 2 × 10 L of water and 1 × 10 L of brine (prepared by dissolving 14 Kg of sodium chloride in 10 L of water) The resulting organic layer (120 L) was dried over sodium sulfate (4 Kg) and concentrated under reduced pressure to give a crude product (6.5 Kg) which was purified by elution with hexane And purified by column chromatography using 60-120 mesh silica gel.The concentration of the pure product gave 5.5 Kg (81%, 3 steps) of bromide 4 as a colorless liquid. |
| With magnesium bromide diethyl etherate; | Synthesis of Linoleyl Bromide (II) A mixture of linoleyl methane sulfonate (6.2 g, 18 mmol) and magnesium bromide etherate (17 g, 55 mmol) in anhydrous ether (300 mL) was stirred under argon overnight (21 hours). The resulting suspension was poured into 300 mL of chilled water. Upon shaking, the organic phase was separated. The aqueous phase was extracted with ether (2*150 mL). The combined ether phase was washed with water (2*150 mL), brine (150 mL), and dried over anhydrous Na2SO4. The solvent was evaporated to afford 6.5 g of colourless oil. The crude product was purified by column chromatography on silica gel (230-400 mesh, 300 mL) and eluted with hexanes. This gave 6.2 g (approximately 100%) of linoleyl bromide (II). 1H NMR (400 MHz, CDCl3) delta: 5.27-5.45 (4H, m, 2*CH=CH), 3.42 (2H, t, CH2Br), 2.79 (2H, t, C=C-CH2-C=C), 2.06 (4H, q, 2* allylic CH2), 1.87 (2H, quintet, CH2), 1.2-1.5 (16H, m), 0.90 (3H, t, CH3) ppm. | |
| 45 g | With magnesium bromide ethyl etherate; In diethyl ether; at 20℃; | EXAMPLE 27 Synthesis of Cationic Lipid A [0372] Preparation of Intermediate A1: (6Z,9Z)-18-bromooctadeca-6,9-diene. [0373] In a 500 mL round-bottom flask equipped with a stir bar, Linoleyl Mesylate (50 g, 145 mmol) was dissolved in diethyl ether (200 mL). Magnesium bromide diethyl etherate (101 g, 392 mmol) was added slowly. Reaction was stirred overnight at room temperature. Brine and ether were added to the mixture in a separatory funnel. The organics were then washed with brine, dried over MgS04, filtered and concentrated under pressure to give crude product mixture. The crude was then purified by silica gel column chromatography eluting with 100% heptane to afford 45 g product. 1H NMR (400 MHz, CDCI3) delta = 5.26 - 5.46 (m, 4 H) 3.42 (t, J=6.90 Hz, 2 H) 2.78 (t, J=6.65 Hz, 2 H) 2.06 (q, J=6.78 Hz, 4 H) 1.86 (dt, J=14.43, 7.09 Hz, 2 H) 1 .21 - 1.49 (m, 16 H) 0.82 - 0.95 (m, 3 H) ppm. |
| 23 g | With lithium bromide; In N,N-dimethyl-formamide; at -10 - 45℃;Inert atmosphere; | A 500 mL glass reactor fitted with an argon inlet was purged with dry argon, charged with 110 mL of DMF and 30 g (87 mmol) of product 3. This reaction mixture was cooled to -10 C. with acetone-dry-ice mixture. To the stirred reaction mixture, a LiBr solution (prepared by dissolving 11.5 g (132 mmol) LiBr in 110 mL of DMF) was added drop wise, while maintaining the reaction temperature below 0 C. After the completion of addition, the reaction mixture was heated to 45 C. and incubated for 18-20 hours under stirring. After the completion of reaction, 300 mL of water was added into the reaction mixture and the reaction mixture was extracted with 240 mL of n-hexane. The organic layers were combined, washed with 2×45 mL of brine solution (prepared by dissolving 59 g NaCl in 45 mL of water), and dried over Na2SO4 (17 g). The organic layer was filtered and condensed using a vacuum pump to remove the organic solvent, resulted in a crude product of 27.5 g. The crude product was purified by column chromatograph using 60-120 mesh silica gel (using n-hexanes as mobile phase), and resulted in 23 g of pure product 4 (the yield of the three steps is 81%). 1H-NMR (CDCl3, 400 MHz), delta=5.41-5.29 (m, 4H), 4.20 (d, 2H), 3.40 (t, 2H), 2.77 (t, 2H), 2.09-2.02 (m, 4H), 1.88-1.00 (m, 2H), 1.46-1.27 (m, 18H), 0.88 (t, 3H). |
| 5.5 kg | With lithium bromide; In N,N-dimethyl-formamide; at -10 - 0℃; for 1.5h;Inert atmosphere; Large scale; | A clean, dry 200 L all glass reactor fitted with argon inlet and thermowell was charged with 25 L of DMF and 7.1 Kg of the crude product from step 2. This mixture was cooled to -10 C. with acetone-dry-ice mixture. To this stirred mixture, a solution of lithium bromide (2.7 Kg, 31.0 mol) in 25 L of DMF was added over a period of 1.5 hrs while maintaining the reaction temperature below 0 C. After completion of the addition, the reaction mixture was stirred at 45 C. for 18-20 h until TLC (10% EtOAc in hexanes, PMA stain) of an aliquot showed complete disappearance of the starting mesylate. The reaction mixture was diluted with 70 L of water and extracted with 57 L of hexanes. The aqueous layer was further extracted with 2×10 L of hexanes and the combined organic layers (approximately 120 L) were washed again with 2×10 L of water and 1×10 L of brine (prepared by dissolving 14 Kg of sodium chloride in 10 L of water). The obtained organic layer (120 L) was dried over sodium sulfate (4 Kg) and concentrated under reduced pressure to obtain the crude product (6.5 Kg). The crude product was purified by column chromatography using 60-120 mesh silica gel using hexanes as eluent. Concentration of the pure product provided 5.5 Kg (81%, three steps) of the bromide 4 as a colorless liquid. 1H NMR (CDCl3, 400 MHz) delta=5.41-5.29 (m, 4H), 4.20 (d, 2H), 3.40 (t, J=7 Hz, 2H), 2.77 (t, J=6.6 Hz, 2H), 2.09-2.02 (m, 4H), 1.88-1.00 (m, 2H), 1.46-1.27 (m, 18H), 0.88 (t, J=3.9 Hz, 3H). 13C NMR (CDCl3) delta=130.41, 130.25, 128.26, 128.12, 34.17, 33.05, 31.75, 29.82, 29.57, 29.54, 29.39, 28.95, 28.38, 27.42, 27.40, 25.84, 22.79, 14.28. |
| 22.8 g | With magnesium bromide ethyl etherate; In diethyl ether; at 20℃; for 24h;Inert atmosphere; | To a solution of linoleyl methanesulfonate (26 g, 75 mmol) in ether (800 mL) was added magnesium bromide ethyl etherate (58.5 g, 226 mmol) under Argon. The reaction mixture was stirred at room temperature for 2 hrs. TLC was used to monitor reaction progress. If not completed, additional magnesium bromide ethyl etherate (14.5 g) was added the reaction mixture and the reaction mixture was stirred at room temperature for 22 hrs. TLC showed the reaction was complete (9/1 hexane/EtOAc). The reaction mixture was filtered, washed with ether (200 mL), hexane (100 mL), and concentrated under reduced pressure to give a residue, which was purified by ISCO (200 g gold silica gel cartridge) eluted with hexane to 10% EtOAc in hexane to give linoleyl bromide (22.8 g, 69.2 mmol, 92 % yield) as a colorless oil. 1H NMR (500 MHz, Chloroform-d) 5 5.42 - 5.31 (m, 4H), 3.41 (t, J= 6.9 Hz, 2H), 2.77 (t,J= 6.6 Hz, 2H), 2.05 (q, J= 6.9 Hz, 4H), 1.85 (p, J= 6.9 Hz, 2H), 1.43 - 1.25 (m, 16H), 0.89 (t, J= 6.8 Hz, 3H). |
| 23 g | With lithium bromide; In N,N-dimethyl-formamide; at 0 - 45℃; | 110ml DMF and 30g product 3 in the glass reactorCool to -10C. 11.5g LiBr dissolved in 110ml DMF,Stir and slowly add dropwise to the reactorAnd keep the temperature of the reaction liquid below 0C. After dropping,The reaction was warmed to 45C and stirred overnight. After the reaction is completed,300 ml water was added and extracted with 240 ml n-hexane.The aqueous phase was further extracted with 2*45 ml of n-hexane. Combine the organic phase,It was washed with water and saturated brine and dried over sodium sulfate (17 g). filter,The organic phase was concentrated to remove the organic solvent to give 27.5 g of crude product.Purified with 60-120 mesh silica gel (n-hexane as the mobile phase),About 23 g of pure product 4 was obtained. |
| 23 g | With lithium bromide; In N,N-dimethyl-formamide; at -10 - 45℃; | 110ml in glass reactor DMF and 30g products 3, Cool to -10 C. 11.5 g of LiBr is dissolved in 110 ml of DMF. Stir and slowly add dropwise to the reactor, And keep the temperature of the reaction solution below 0 C. After the addition is completed, The reaction solution was heated to 45 C. Stir overnight. After completion of the reaction, 300 ml of water was added and extracted with 240 ml of n-hexane, and the aqueous phase was further extracted with 2*45 ml of n-hexane. The combined organic layers were washed with water and aq.After filtration, the organic phase was concentrated to remove organic solvent to give a crude material (27.5 g). Purification with 60-120 mesh silica gel (n-hexane as mobile phase) gave about 23 g of pure product 4. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 2 g | Hexane (30 ml) and potassium hydroxide (3.1 g, 54.4 mmol) were added to a screw tube, and <strong>[623-57-4]3-(dimethylamino)-1,2-propanediol</strong> (0.72 g, 6.04 mmol: DAP) was dropped in a nitrogen atmosphere under agitation. Thereafter, linoleyl methane sulfonate (5.0 g, 14.5 mmol) obtained in Production example 1 was dropped, and agitation was performed at room temperature. After 48 hours, the reaction was terminated because remaining linoleyl methane sulfonate became 0.9percent (degree of conversion: 65.0percent, integrated value of isomer: 0.017). [0056] The reaction solution was subjected to decantation, and a supernatant solution was added to a phosphoric acid buffer (75 ml) with a pH of 6, followed by agitation. After standing to separate into layers, a water layer was discarded. Acetonitrile (20 ml) was added. After agitation and standing, a lower layer (acetonitrile layer) was removed. Acetonitrile (20ml) was added once again and the same operation was performed again. A hexane layer was dehydrated with magnesium sulfate (1.0 g) and was filtrated. Subsequently, solvent was removed, so as to obtain a roughly refined product (3.3 g). This was refined with a silica gel (DAISOGEL IR-60-25/40) column by using a hexane solution containing 5 to 20 percent by volume of ethyl acetate, so that an objective substance (2.0 g) was obtained (integrated value of isomer: 0.015). [0057] The resulting objective substance was analyzed with 1H-NMR (600 MHz, CDCl3) and was ascertained to be the objective substance on the basis of 1H-NMR (600 MHz, CDCl3): delta 5.42 to 5.30 (m, 8H, 4x CH=CH), 3.59 to 3.44 (m, 7H, OCH, 3x OCH2), 2.79 (t, 4H, 2x =CHCH2CH=), 2.40 (m, 2H, NCH2), 2.28 (s, 6H, 2x NCH3), 2.06 (q, 8H, 4x CH2CH2CH=), 1. 56 (m, 4H, 2x CH2CH2O), 1.41 to 1.28 (m, 32H), 0.89 (t, 6H, 2x CH2CH3). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 93% | With magnesium bromide diethyl etherate; In diethyl ether; at 20℃; for 16h; | To a solution of (6Z,9Z)-18-(methylsulfonyl)octadeca-6,9-diene (10.0 g, 29.0 mmol) in diethyl ether (372 mL) was added magnesium bromide ethyl etherate (22.5 g, 87.1 mmol). The reaction was let stir at room temperature for 16 hours. The mixture was quenched by the addition of water and extracted with diethyl ether. The combined organic layers were washed with 1% K2CO3, brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. Purification by ISCO silica flash chromatography provided (6Z,9Z)-18-bromooctadeca- 6,9-diene (8.9 g, 93%).1H NMR (300 MHz, CDCl3) delta: ppm 5.36 (m, 4H); 3.41 (t, 2H); 2.77 (t, 2H); 2.05 (q, 4H); 1.86 (m, 2H); 1.48-1.22 (br. m, 16H); 0.89 (t, 3H). |