4102-60-7|18-Bromo-6,9-octadecadiene| Ambeed

Structure of 4102-60-7

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Quality Control of [ 4102-60-7 ] Purity: 95% SDS Specification

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Product Details of [ 4102-60-7 ]

CAS No. :	4102-60-7
Formula :	C₁₈H₃₃Br
M.W :	329.36
SMILES Code :	CCCCC/C=C/C/C=C/CCCCCCCCBr
MDL No. :	MFCD00034591
InChI Key :	SBRPUFDSMGABKD-AVQMFFATSA-N
Pubchem ID :	6001965

Safety of [ 4102-60-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 4102-60-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	19
Num. arom. heavy atoms	0
Fraction Csp3	0.78
Num. rotatable bonds	14
Num. H-bond acceptors	0.0
Num. H-bond donors	0.0
Molar Refractivity	95.56
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	0.0 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	4.85
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	8.69
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	7.19
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	6.1
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	7.33
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	6.83

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-6.43
Solubility	0.000122 mg/ml ; 0.000000369 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-8.57
Solubility	0.000000889 mg/ml ; 0.0000000027 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-6.54
Solubility	0.0000961 mg/ml ; 0.000000292 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	Low
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	Yes
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-2.14 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	1.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	1.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	1.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	2.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<2.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	4.1

Application In Synthesis of [ 4102-60-7 ]

* 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.

Downstream synthetic route of [ 4102-60-7 ]

[ 4102-60-7 ] Synthesis Path-Downstream 1~35

1
[ 506-43-4 ]
[ 4102-60-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0℃;	In a round bottom flask was introduced triphenylphosphine (1.90 g, 7.3 mmol), carbon tetrabromide (2.16 g, 6.5 mmol), and dichloromethane (DCM) (15 mL) was added at 0C, the mixture is let stirred for 10 minutes (orange solution), then (9Z, 12Z)-octadecadien-1-ol (965.9 mg, 3.6 mmol) in DCM (10 mL) was transferred on the mixture via cannula at 0C. A white precipitate was formed. The reaction mixture was let warm up overnight; then it was filtered over celite and concentrated under reduced pressure. The product was purified by a column chromatography on SiO2 (petroleum ether/ ethyl acetate (9:1), Rf = 0.90). mpure = 0.96 g. Aspect: colorless oil. Yield: 80%. 1H NMR (500 MHz, CDCl3) delta (ppm): 5.42-5.34 (m, 4H), 3.43 (t, 2H, J = 6.9 Hz), 2.79 (m, 2H), 2.07 (m, 4H), 1.88 (m, 2H), 1.45 (m, 2H), 1.39-1.31 (m, 14H), 0.92 (t, 3H, J = 7.0 Hz) 13C {1H} NMR (126 MHz, CDCl3) delta (ppm): 130.20, 130.10, 128.01, 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 C18H32Br [M-H]+ 327.1681, found 327.1682.
66%	With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at 0 - 20℃;	To a solution of (9Z, 12Z)-octadeca-9, 12-dien- l -ol (5 g, 1 8.76 mmol) and PPh3 (5.22 g, 19.89 mmol) in DCM (60 mL) at 0 C, was added NBS (3.87 g, 21 .77 mmol) in one portion. The reaction mixture was allowed to stir at 0 C for 1 hour and then allowed to slowly warm to room temperature and allowed to stir for 1 hour. 240 mL of hexanes was added to the reaction mixture, filtered through a silica gel plug and concentrated in vacuo. 200 mL of hexanes was added to the reaction mixture, filtered through a silica gel plug and concentrated in vacuo to afford (6Z,9Z)- 8-bromooctadeca-6,9-diene (4.06 g, 12.33 mmol, 66%). NMR (300 MHz, CDC13) delta: ppm 5.45-5.3 1 (br. m, 4H); 3.43 (t, 2H); 2.80 (m, 2H); 2.1 1 - 2.04 (br. m, 411); 1 .88 (m, 211); 1 .47-1 .33 (br. m, 1 H); 0.92 (m, 3H).

References: [1]Journal of the Chemical Society. Perkin transactions I,1993,p. 1183 - 1190.
[2]Patent: EP3575283,2019,A1 .Location in patent: Paragraph 0137; 0139-0140; 0145.
[3]Patent: WO2017/99823,2017,A1 .Location in patent: Page/Page column 337-338.
[4]Journal of the Chemical Society,1961,p. 3854 - 3858.
[5]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[6]Patent: US9120938,2015,B2 .
[7]Patent: US2015/272886,2015,A1 .
[8]Patent: US9186325,2015,B2 .
[9]Patent: US9394234,2016,B2 .
[10]Patent: JP2016/84297,2016,A .
[11]Patent: WO2017/62862,2017,A2 .
[12]Patent: WO2017/112865,2017,A1 .
[13]Patent: US9701623,2017,B2 .
[14]Patent: US2017/273905,2017,A1 .
[15]Patent: WO2017/210647,2017,A1 .
[16]Patent: CN105085292,2017,B .
[17]Patent: CN105085437,2018,B .
[18]Patent: WO2018/232120,2018,A1 .

2
[ 108753-59-9 ]
[ 4102-60-7 ]
[ 66252-65-1 ]

References: [1]Journal of the Chemical Society,1961,p. 3854 - 3858.

3
[ 4102-60-7 ]
[ 109-89-7 ]
[ 64875-28-1 ]

References: [1]Pharmaceutical Chemistry Journal,1977,vol. 11,p. 1238 - 1242.
Khimiko-Farmatsevticheskii Zhurnal,1977,vol. 11,p. 81 - 86.

4
[ 150630-52-7 ]
[ 4102-60-7 ]
methyl (Z,Z)-hexacosa-17,20-dienoate [ No CAS ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1993,p. 1183 - 1190.

5
[ 4102-60-7 ]
[ 106689-05-8 ]
methyl (Z,Z)-tetratriaconta-25,28-dienoate [ No CAS ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1993,p. 1183 - 1190.

6
[ 4102-60-7 ]
[ 60839-74-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; In acetone; at 55℃; for 2h;Inert atmosphere; Reflux;	Intermediate 127b: (6Z,9Z)-18-iodooctadeca-6,9-diene To a solution of intermediate 127a (14.0 g, 42.659 mmol) in acetone (150 mL) in a RBF charged with a magnetic stir bar under N2 was added sodium iodide (12.7 g, 85.3 mmol). The reaction was heated to reflux (55 C) for 2 hours, after which it was cooled to room temperature and the solids were filtered off. The solvent was evaporated and the remaining solids were removed by dissolution in H20 (100 mL) and extraction with DCM (2 x 200 mL). The combined organic layers were dried over Na2S04 and evaporated to dryness to afford the desired product as a crude pale brown liquid (15.5 g, 97%). This material was used in the next step without further purification. TLC: Rf = 0.6 (100% pentane), PMA active.

References: [1]Journal of the Chemical Society. Perkin transactions I,1993,p. 1183 - 1190.
[2]Patent: WO2015/95346,2015,A1 .Location in patent: Page/Page column 208-209.

7
[ 112-63-0 ]
[ 4102-60-7 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1993,p. 1183 - 1190.

8
[ 4102-60-7 ]
[ 64875-25-8 ]

References: [1]Pharmaceutical Chemistry Journal,1977,vol. 11,p. 1238 - 1242.
Khimiko-Farmatsevticheskii Zhurnal,1977,vol. 11,p. 81 - 86.

9
N,N-dimethoxycarbonylmethyl-m-hydroxyaniline [ No CAS ]
N-(3-hydroxyphenyl-N-(2-methoxy-2-oxoethyl)glycine methyl ester [ No CAS ]
ethyl acetate n-hexane [ No CAS ]
[ 13044-38-7 ]
[ 4102-60-7 ]
N-(2-methoxy-2-oxoethyl)-N-[3-[(Z)-(9-octadecenyl)oxy]phenyl]glycine methyl ester [ No CAS ]
N-(2-methoxy-2-oxoethyl)-N-[3-[(9Z,12Z)-(9,12-octadecadienyl]oxy]phenyl]glycine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; potassium carbonate; In ethyl acetate; N,N-dimethyl-formamide; acetone;	EXAMPLE 48 N-(2-Methoxy-2-oxoethyl)-N-[3-[(Z)-(9-octadecenyl)oxy]phenyl]glycine methyl ester A mixture of 0.24 g (0.95 mmol) of N-(3-hydroxyphenyl)-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 0.33 g (1 mmol) of oleyl bromide, 0.15 g (1 mmol) of sodium iodide and 0.41 g (3 mmol) of potassium carbonate in 10 ml of acetone was stirred at reflux under argon for 18 hours. DMF (5 ml) was added and reflux was continued for 3 days. The solvents were removed at reduced pressure and the residue was dissolved in ethyl acetate. The extract was dried and concentrated at reduced pressure to an oil which was purified by chromatography on 230-400 mesh silica gel using 25% ethyl acetate-hexane to give 0.25 g (50% yield, mp 36-37) of N-(2-methoxy-2-oxoethyl)-N-[3-[(Z)-(9-octadecenyl)oxy]phenyl]glycine methyl ester. The nmr and spectra were consistent with the structure. Using this procedure, the reaction of N-(3-hydroxyphenyl-N-(2-methoxy-2-oxoethyl)glycine methyl ester with <strong>[4102-60-7]linoleyl bromide</strong> gave N-(2-methoxy-2-oxoethyl)-N-[3-[(9Z,12Z)-(9,12-octadecadienyl]oxy]phenyl]glycine methyl ester as an oil. The structure was confirmed by nmr and mass spectra.

References: [1]Patent: US5324747,1994,A .

10
[ 79-37-8 ]
[ 60-33-3 ]
[ 4102-60-7 ]
[ 1192363-15-7 ]
[ 1192363-14-6 ]

Yield	Reaction Conditions	Operation in experiment
	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)+.

References: [1]Patent: US2009/263407,2009,A1 .

11
[ 4102-60-7 ]
[ 109-94-4 ]
[ 1169768-27-7 ]
[ 1169768-28-8 ]

Yield	Reaction Conditions	Operation in experiment
1.9 g; 78%		Synthesis of Compound 6bTo a flame dried 500 mL RB flask, freshly activated Mg turnings (2.4 g, 100 mmol) were added and the flask was equipped with a magnetic stir bar, an addition funnel and a reflux condenser. This set-up was degassed and flushed with argon and 10 mL of anhydrous ether was added to the flask via syringe. The bromide 3 (26.5 g, 80.47 mmol) was dissolved in anhydrous ether (50 mL) and added to the addition funnel. About 5 mL of this ether solution was added to the Mg turnings while stirring vigorously. An exothermic reaction was noticed (to confirm/accelerate the Grignard reagent formation, 5 mg of iodine was added and immediate decolorization was observed confirming the formation of the Grignard reagent) and the ether started refluxing. The rest of the solution of the bromide was added dropwise while keeping the reaction under gentle reflux by cooling the flask in water. After the completion of the addition the reaction mixture was kept at 35 C. for 1 h and then cooled in ice bath. Ethyl formate (2.68 g, 36.2 mmol) was dissolved in anhydrous ether (40 mL) and transferred to the addition funnel and added dropwise to the reaction mixture with stirring. An exothermic reaction was observed and the reaction mixture started refluxing. After the initiation of the reaction the rest of the ethereal solution of formate was quickly added as a stream and the reaction mixture was stirred for a further period of 1 h at ambient temperature. The reaction was quenched by adding 10 mL of acetone dropwise followed by ice cold water (60 mL). The reaction mixture was treated with aq. H2SO4 (10% by volume, 300 mL) until the solution became homogeneous and the layers were separated. The aq. phase was extracted with ether (2×100 mL). The combined ether layers were dried (Na2SO4) and concentrated to get the crude product which was purified by column (silica gel, 0-10% ether in hexanes) chromatography. The slightly less polar fractions were concentrated to get the formate 6a (1.9 g) and the pure product fractions were evaporated to provide the pure product 6b as a colorless oil (14.6 g, 78%).
40%; 8%		[0157] The intermediate compounds (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31- tetraen-19-yl formate (6) and (6Z,9Z,28Z,3 lZ)-heptatriaconta-6,9,28,3 l-tetraen-19-ol respectively identified as compounds (6) and (7) in Reaction 2 above were prepared in an oven dried 3-neck 500mL flask that was charged with Mg (0.5g, 20.83mmol, 1.37 eq.) and (one crystal) under argon. The flask was degassed on a high-vacuum line, then flushed with argon (the process was repeated four times) and then stirred at room temperature for approximately 5 minutes. Anhydrous ether (22mL) was added to this flask and the slurry stirred for approximately 10 minutes. Next, 5g (15.2mmol, 1 eq.) of compound (5) (<strong>[4102-60-7]linoleyl bromide</strong>) was added under argon (color change was observed after the addition of approximately 4.5mL of compound (5)) and the reaction stirred at room temperature. An exothermic reaction was observed after stirring for approximately 5 minutes at room temperature. Thus, the mixture was cooled using an ice-water bath for approximately 2 minutes, then the ice-bath was removed and the reaction mixture stirred at room temperature for 2 hours, resulting in an ash colored reaction mixture and not all of the Mg was consumed. The mixture was cooled to 0 C and the HC02Et (0.58 mL, 7.17mmol, 0.47 eq.) was added dropwise directly into the solution. After stirring at room temperature for 3 hours (product was observed after 1 hour by MS and TLC) the mixture was decanted and the Mg turnings washed with ether. The combined washings were diluted with ether (lOOmL), washed with 10% H2S04 (2 X 50mL), water, brine and then dried ( a2S04). The solution was filtered, concentrated and the residue purified by silica-gel column chromatography. [0158] 5-7% ether in hexanes eluted the alcohol (compound (7)) from the residue. Yield: 0.34g (8%). Compound 7: NMR (300 MHz, CDC13): delta 5.38-5.31 (m, 8H), 3.58 (br s, 1H), 2.76 (t, J= 6 Hz, 4 H), 2.04 (q, J= 6.8 Hz, 8H), 1.39-1.26 (m, 40H), 0.88 (t, J= 6.8 Hz, 6H). APCI[M+H] 527, 511 (-H20). [0159] 2% ether in hexanes eluted the formate (compound (6)) from the residue. Yield: 1.7g (40%). Compound 6: XH NMR (300 MHz, CDC13): delta 8.08 (s, 1H), 5.42-5.28 (m, 8H), 4.99-4.95 (m, 1H), 2.76 (t, J= 6 Hz, 4 H), 2.04 (q, J= 6.6 Hz, 8H), 1.39-1.26 (m, 40H), 0.88 (t, J= 6.6 Hz, 6H). APCI[M+H] 557.
		Synthesis of Dilinoleyl Methanol (III) To a suspension of Mg turnings (0.45g, 18.7 mmol) with one crystal of iodine in 200 ml_ of anhydrous ether under nitrogen was added a solution of <strong>[4102-60-7]linoleyl bromide</strong> (II) in 50 ml_ of anhydrous ether at room temperature. The resulting mixture was refluxed under nitrogen overnight. The mixture was cooled to room temperature. To the cloudy mixture under nitrogen was added dropwise at room temperature a solution of ethyl formate (0.65g, 18.7 mmol) in 30 ml_ of anhydrous ether. Upon addition, the mixture was stirred at room temperature overnight (20 hours). The ether layer was washed with 10% H2SO4 aqueous solution (100 ml_), water (2 x 100 ml_), brine (150 ml_), and then dried over anhydrous Na2SO4. Evaporation of the solvent gave 5.Og of pale oil. Column chromatography on silica gel (230-400 mesh, 300 ml_) with 0- 7% ether gradient in hexanes as eluent afforded two products, dilinoleyl methanol (2.Og, III) and dilinoleylmethyl formate (1.4g, IV). 1 H NMR (400 MHz, CDCI3) for dilinoleylmethyl formate (IV) delta: 8.10 (1 H, s, CHO), 5.27-5.45 (8H, m, 4 x CH=CH), 4.99 (1 H, quintet, OCH), 2.78 (4H, t, 2 x C=C-CH2-C=C), 2.06 (8H, q, 4 x allylic CH2), 1.5-1.6 (4H, m, 2 x CH2), 1.2-1.5 (32H, m), 0.90 (6H, t, 2 x CH3) ppm.

		To a suspension of Mg turnings (0.45 g, 18.7 mmol) with one crystal of iodine in 200 mL of anhydrous ether under nitrogen was added a solution of <strong>[4102-60-7]linoleyl bromide</strong> (II) in 50 mL of anhydrous ether at room temperature. The resulting mixture was refluxed under nitrogen overnight. The mixture was cooled to room temperature. To the cloudy mixture under nitrogen was added dropwise at room temperature a solution of ethyl formate (0.65 g, 18.7 mmol) in 30 mL of anhydrous ether. Upon addition, the mixture was stirred at room temperature overnight (20 hours). The ether layer was washed with 10% H2SO4 aqueous solution (100 mL), water (2×100 mL), brine (150 mL), and then dried over anhydrous Na2SO4. Evaporation of the solvent gave 5.0 g of pale oil. Column chromatography on silica gel (230-400 mesh, 300 mL) with 0-7% ether gradient in hexanes as eluent afforded two products, dilinoleyl methanol (2.0 g, III) and dilinoleylmethyl formate (1.4 g, IV). 1H NMR (400 MHz, CDCl3) for dilinoleylmethyl formate (IV) : 8.10 (1H, s, CHO), 5.27-5.45 (8H, m, 4×CHCH), 4.99 (1H, quintet, OCH), 2.78 (4H, t, 2×CC-CH2-CC), 2.06 (8H, q, 4×allylic CH2), 1.5-1.6 (4H, m, 2×CH2), 1.2-1.5 (32H, m), 0.90 (6H, t, 2×CH3) ppm
		A 250 mL three-neck reactor was purged with dry argon, into which 2.21 g (92 mmol) of activated Mg and 12 mL of anhydrous diethyl ether were added. Product 4 (20 g, 61 mmol) was dissolved in anhydrous diethyl ether (40 mL). Under the protection of argon, 8 mL of the product 4 solution was added to the reactor, together with 0.2 mL (2.8 mmol) of dibromomethane. Using a water bath, the temperature of the reaction mixture was increased to 40 C. After the start of the reaction, the heating resource was removed, and the remaining solution (32 mL) was added drop wise to the reactor within 1 hour, while maintaining a gentle reflux of the mixture. After the completion of the addition, the reaction mixture was heated to keep reflux for 1 hour. After the raw materials were completely consumed, the reaction mixture was cooled to below 10 C. using an ice-bath, in which a diethyl ether solution of ethyl formate (prepared by dissolving 2.2 mL of ethyl formate in 32 mL of diethyl ether) was added slowly. The reaction mixture was warmed to room temperature and incubated for 1 hour under stirring. Then ice-cold water (56 mL) and 10% sulfuric acid solution (prepared by dissolving 27.2 mL of sulfuric acid in 272 of ice-cold water) were added, from which the organic layers were separated. The aqueous layer was extracted with diethyl ether (3×80 mL). The combined organic layers were washed with brine solution (80 ml), dried over sodium sulfate (16 g) and filtered. The organic layer was concentrated and organic solvent was removed with a vacuum pump to obtain a crude product (a mixture of alcohols and formate). This crude product was redissolved in 100 ml of THF. To this a solution of NaOH (prepared by dissolving 7.5 g of NaOH in 150 mL of water) was added and the contents were heated to and incubated at 65 C. for 18 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature and extracted with diethyl ether (3×100 mL) The combined organic layers were washed with brine solution (40 mL), dried over sodium sulfate (40 g) and filtered. The organic layer was concentrated. The thus obtained crude product was purified using a 60-120 mesh silica gel (4% ethyl ether in hexane), to obtain the pure product 6a (11.6 g, 80% yield). 1H-NMR (CDCl3, 400 MHz), delta=5.47-5.24 (m, 8H), 3.70-150 (m, 1H), 2.85-2.66 (m, 4H), 2.12-1.91 (m, 9H), 1.55-1.17 (m, 46H), 0.90-0.80 (m, 6H).
1.4 g; 2 g		[0205] To a suspension of Mg turnings (0.45g, 18.7 mmol) with one crystal of iodine in 200 mL of anhydrous etherunder nitrogen was added a solution of <strong>[4102-60-7]linoleyl bromide</strong> (II) in 50 mL of anhydrous ether at room temperature. Theresulting mixture was refluxed under nitrogen overnight. The mixture was cooled to room temperature. To the cloudymixture under nitrogen was added dropwise at room temperature a solution of ethyl formate (0.65g, 18.7 mmol) in 30mL of anhydrous ether. Upon addition, the mixture was stirred at room temperature overnight (20 hours). The ether layerwas washed with 10% H2SO4 aqueous solution (100 mL), water (2 x 100 mL), brine (150 mL), and then dried overanhydrous Na2SO4. Evaporation of the solvent gave 5.0g of pale oil. Column chromatography on silica gel (230-400mesh, 300 mL) with 0-7% ether gradient in hexanes as eluent afforded two products, dilinoleyl methanol (2.0g, III) anddilinoleylmethyl formate (1.4g, IV). 1 H NMR (400 MHz, CDCl3) for dilinoleylmethyl formate (IV) delta: 8.10 (1 H, s, CHO),5.27-5.45 (8H, m, 4 x CH=CH), 4.99 (1 H, quintet, OCH), 2.78 (4H, t, 2 x C=C-CH2-C=C), 2.06 (8H, q, 4 x allylic CH2),1.5-1.6 (4H, m, 2 x CH2), 1.2-1.5 (32H, m), 0.90 (6H, t, 2 x CH3) ppm.
		A clean dry 200 L total glass reactor fitted with an argon inlet, a reflux condenser and a thermowell was degassed and purged with argon. The reactor was charged with 277 g (11.3 mol) of active magnesium and then 1.5 L of anhydrous ether. The reactor was again evacuated three times and purged with argon. Bromide 4 (2.5 Kg, 7.6 mol) was dissolved in 5 L of anhydrous ether under argon, 1 L of this solution was added to the reactor and then 25 mL (0.35 mol) of dibromomethane was added. The contents of the reactor were heated to 40 C. using a water bath (refluxing after foaming was observed, indicating the onset of Grignard reagent production). After initiating the reaction, the heating apparatus was removed from the reactor and the remaining 4 L of bromide was slowly added over a period of 2 hours 30 minutes while maintaining a gentle reflux of the mixture. After addition was complete, the reaction mixture was again heated to reflux (bath temperature 45 C.) for 1 hour, after which an aliquot of the reaction mixture was quenched with water and analyzed by TLC (hexane, PMA staining). This indicated complete disappearance of the starting bromide. The reaction mixture was cooled to below 10 C. using an ice bath and ethyl formateEther solution (275 mL in 4 L of ether) was added over 2 h 30 min and after addition was complete the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was cooled to 10 C., acetone (1.15 L) was slowly added to the mixture and then prepared by dissolving 7 L of ice cold water and 3.4 L of sulfuric acid with 34 L of ice cold water ) 10% sulfuric acid solution were added. The product was extracted with 3 × 10 L of ether and the combined organic layers were washed with 10 L of brine and dried over sodium sulfate (2 Kg). Concentration of the organic layer under reduced pressure gave the crude product (2 Kg) as a mixture of required dilinoleyl alcohols along with traces of O-formylated product. This crude product was redissolved in THF (4 L) and loaded into a 20 L glass reactor. To this was added a NaOH solution (0.934 Kg dissolved in 8 L of ice cold water) and the contents were heated at 65 C. for 18 h and then subjected to O-formylation by TLC (10% ether in hexane) Indicating that the product was completely converted to the desired dilinoleyl methanol. The reaction mixture was cooled, extracted with ether (3 × 4 L) and the combined organic layers were washed withWashed with 5 L of brine and dried over sodium sulfate (4 Kg). After filtration, the organic layer was concentrated to give a crude product. The crude product thus obtained was purified by column chromatography using silica gel of 60-120 mesh with 4% ether in hexane. Concentration of the pure product fractions gave pure 6 (1.45 Kg, 80%) as a colorless liquid
		In a three-necked flask, 2.21 g of Mg and 12 ml of anhydrous ether were added. The reactor was filled with argon. 20g of product 4 dissolved in40 ml of anhydrous ether. Under argon protection, 8 ml of this solution was added dropwise to the reactor and 0.2 ml of dibromomethane was further added. The reaction solution was heated to 40C in a water bath. After the start of the reaction, the heat source was removed and the remaining 32 ml of solution was added dropwise to the reactor.The composition maintains a slight reflux condition. After completion of the addition, the reaction was heated to maintain reflux. After the reaction is completed,Reaction solutionIce bath cooling below 10C and ethyl formate in diethyl ether (2.2 ml in 32 ml diethyl ether) was added slowly. After addingAfterwards, the reaction was overnight at room temperature. Then 56 ml of ice water and 10% sulfuric acid solution were added, the organic phase was separated and the aqueous phase was extracted with ether.The organic phases are combined, washed with brine and dried over sodium sulfate. Filter and concentrate the organic phase to remove the organic solvent to obtain the crude product (alcohol and AAcid ester mixture) 16g. The crude product was dissolved with 100 ml THF, NaOH solution (7.5 g dissolved in 150 ml water) was added and heated to 65C.The reaction was 18 hours. After the reaction was completed, the reaction was cooled to room temperature and extracted with ether. The organic phases were combined and washed with 40 ml of brine.Di. Dry over sodium sulfate. Filter and concentrate the organic phase. The crude product was purified with 60-120 mesh silica gel (4% ether/n-hexane) to give pure product.DLM6a (11.6 g) (yield 40%).
		2.21 g of Mg and 12 ml of anhydrous diethyl ether were added to the three-necked flask. The reactor was filled with argon. 20 g of product 4 was dissolved in 40 ml of anhydrous diethyl ether. Under argon protection, 8 ml of this solution was added dropwise to the reactor, and 0.2 ml of dibromomethane was continuously added. The reaction solution was warmed to 40 C in a water bath. After the reaction started, the heat source was removed, and the remaining 32 ml of the solution was added dropwise to the reactor, and the mixture was kept under a slight reflux. After the completion of the dropwise addition, the mixture was heated to maintain a reflux state. After completion of the reaction, the reaction solution was cooled to 10 C or less with an ice bath, and then a solution of ethyl formate in diethyl ether (2.2 ml in 32 ml of diethyl ether) was slowly added. After the completion of the dropwise addition, the reaction was allowed to proceed overnight at room temperature. Then, 56 ml of ice water and a 10% sulfuric acid solution were added, the organic phase was separated, and the aqueous phase was extracted with diethyl ether. The organic phases were combined, washed with brine and dried over sodium sulfate. Filtration and concentration of the organic phase to remove the organic solvent to obtain a crude product of 16 g (Alcohol and formate mixture). The crude product was dissolved in 100 ml of THF, NaOH solution (7.5 g dissolved in 150 ml of water) was added, and the mixture was heated to 65 C for 18 hours. After the reaction was completed, the reaction was cooled to room temperature, then it was extracted with diethyl ether and the organic phases were combined and washed with 40 ml brine. Dried over sodium sulfate. Filtrated and concentrated the organic phase. The crude product was purified with 60-120 mesh silica gel (4% diethyl ether / n-hexane) to give purified product DLM6a (11.6 g) (yield 40%).

References: [1]Patent: US9186325,2015,B2 .Location in patent: Page/Page column 90; 91.
[2]Patent: WO2013/149140,2013,A1 .Location in patent: Paragraph 0157; 0158; 0159.
[3]Patent: WO2010/42877,2010,A1 .Location in patent: Page/Page column 86; 87.
[4]Patent: US2012/264810,2012,A1 .Location in patent: Page/Page column 42-43.
[5]Patent: US2015/272886,2015,A1 .Location in patent: Paragraph 0039.
[6]Patent: EP2224912,2016,B1 .Location in patent: Paragraph 0203;0205.
[7]Patent: JP5819291,2015,B2 .Location in patent: Paragraph 0447; 0450.
[8]Patent: CN105085292,2017,B .Location in patent: Paragraph 0053; 0071-0074; 0084-0086.
[9]Patent: CN105085437,2018,B .Location in patent: Paragraph 0052; 0070; 0081; 0082; 0083.

12
[ 51154-39-3 ]
[ 4102-60-7 ]

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 (2150 mL). The combined ether phase was washed with water (2150 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, 2CH=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.

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13
[ 4102-60-7 ]
[ 109-94-4 ]
[ 1169768-28-8 ]

Yield	Reaction Conditions	Operation in experiment
86%		To a flame dried 500 mL RB flask, freshly activated 16 Mg turnings (2.4 g, 100 mmol) were added and the flask was equipped with a magnetic stir bar, an addition funnel and a reflux condenser. This set-up was degassed and flushed with argon and 10 mL of anhydrous ether was added to the flask via syringe. The bromide (13 3) (26.5 g, 80.47 mmol) was dissolved in anhydrous ether (50 mL) and added to the addition funnel. About 5 mL of this ether solution was added to the Mg turnings while stirring vigorously. An exothermic reaction was noticed (to confirm/accelerate the Grignard reagent formation, 5 mg of 17 iodine was added and immediate decolorization was observed confirming the formation of the Grignard reagent) and the ether started refluxing. The rest of the solution of the bromide was added dropwise while keeping the reaction under gentle reflux by cooling the flask in 12 water. After the completion of the addition the reaction mixture was kept at 35 C. for 1 h and then cooled in ice bath. 18 Ethyl formate (2.68 g, 36.2 mmol) was dissolved in anhydrous ether (40 mL) and transferred to the addition funnel and added dropwise to the reaction mixture with stirring. An exothermic reaction was observed and the reaction mixture started refluxing. After the initiation of the reaction the rest of the ethereal solution of formate was quickly added as a stream and the reaction mixture was stirred for a further period of 1 h at ambient temperature. The reaction was quenched by adding 10 mL of 19 acetone dropwise followed by ice cold water (60 mL). The reaction mixture was treated with aq. H2SO4 (10% by volume, 300 mL) until the solution became homogeneous and the layers were separated. The aq. phase was extracted with ether (2×100 mL). The combined ether layers were dried (Na2SO4) and concentration of the organic layer over reduced pressure provided the crude product as a mixture of required dilinoleylmethanol along with minor amounts of O-formylated product. This crude product was re-dissolved in 20 THF (100 mL) and treated with ice-cold 21 aqueous NaOH (10%) and heated at 40 C. for 18 h after which the TLC (10% ether in hexanes) showed the complete conversion of the O-formylated product to the required dilinoleylmethanol. The reaction mixture was cooled and was extracted with ether (3×100 mL) and the combined organic layers were washed with brine and dried over sodium sulfate. Filtration followed by concentration of the organic layer provided the crude product. The thus obtained crude product was purified by column chromatography using 60-120 mesh silica gel using 4% ether in hexanes. Concentration of the pure product fractions provided the pure 22 product (15.4 g, 86%) as a colorless liquid. NMR (400 MHz, CDCl3) delta 5.47-5.24 (m, 8H), 3.56 (dd, J=6.8, 4.2, 1H), 2.85-2.66 (m, 4H), 2.12-1.91 (m, 9H), 1.50-1.17 (m, 46H), 0.98-0.76 (m, 6H). 13C NMR (101 MHz, CDCl3) delta 130.41, 130.37, 128.18, 128.15, 77.54, 77.22, 76.91, 72.25, 37.73, 31.75, 29.94, 29.89, 29.83, 29.73, 29.58, 29.53, 27.46, 27.43, 25.89, 25.86, 22.80, 14.30.
81%		General procedure: Step 2: A 1 liter RBF was charged with magnesium turnings (11.1 g, 463 mmol), anhydrous THF (65 mL) and stir-bar and flushed with nitrogen. In a separate flask, a solution of <strong>[4102-60-7]linoleyl bromide</strong> (140 g, 425 mL) in anhydrous THF (150 mL) was prepared, and 20 mL of this solution added to the magnesium. When most of the heat had dissipated, the remainder of the bromide was added over a period of 15 minutes. Temperature was then maintained at 45 C. for 4 h. The reaction was then cooled (0 C.). Using a dropping funnel, a solution of ethyl formate (32.4 g, 438 mmol) in anhydrous THF (150 mL) was added over a 40 minute period. The reaction was stirred overnight at room temperature. The reaction was cooled to -15 C. and 5N HCl (185 mL) added slowly. The mixture was transferred to a 2 L separating funnel separated. Water (150 mL) and hexane (150 mL) were added, the mixture washed, and again the aqueous removed. The organic was washed a final time with water (150 mL) and then concentrated to a yellow oil. The yellow oil was stirred with a mixture of EtOH (210 mL), water (30 mL) and KOH (15.8 g) for 1.5 h at room temp. The EtOH was evaporated and the residue treated with hexane (50 mL). 5N HCl (200 mL) was added via dropping funnel. The organic was washed with water (2×50 mL) evaporated, dried and purified by chromatography (0-5% EtOAc in hexane, 91 g, 81%).
81%		STEP 2: Al liter REF was charged with magnesium turnings (11.1 g, 463 mmol), anhydrous THF (65 mE) and stir-bar and flushed with nitrogen. In a separate flask, a solution of <strong>[4102-60-7]linoleyl bromide</strong> (140 g, 425 mE) in anhydrous THF (150 mE) was prepared, and 20 mE of this solution added to the magnesium. When most of the heat had dissipated, the remainder of the bromide was added over a period of 15 minutes. Temperature was then maintained at 45 C. for 4 h. The reaction was then cooled (0 C.). Using a dropping thnnd, a solution of ethyl formate (32.4 g, 438 mmol) in anhydrous THF (150 mE) was added over a 40 minute period. The reaction was stirred overnight at room temperature. The reaction was cooled to -15 C. and SN HC1 (185 mE) added slowly. The mixture was transferred to a 2 E separating thnnel separated. Water (150 mE) and hexane (150 mE) were added, the mixture washed, and again the aqueous removed. The organic was washed a final time with water (150 mE) and then concentrated to a yellow oil. The yellow oil was stirred with a mixture of EtOR (210 mE), water (30 mE) and KOR (15.8 g) for 1.5 h at room temp. The EtOR was evaporated and the residue treated with hexane (50 mE). SN HC1 (200 mE) was added via dropping funnel. The organic was washed with water (2x50 mE) evaporated, dried and purified by chromatography (0-5% EtOAc in hexane, 91 g, 81%).

80%		A clean dry 200 L total glass reactor fitted with an argon inlet, a reflux condenser and a thermowell was degassed and purged with argon. The reactor was charged with 277 g (11.3 mol) of active magnesium and then 1.5 L of anhydrous ether. The reactor was again evacuated three times and purged with argon. Bromide 4 (2.5 Kg, 7.6 mol) was dissolved in 5 L of anhydrous ether under argon, 1 L of this solution was added to the reactor and then 25 mL (0.35 mol) of dibromomethane was added. The contents of the reactor were heated to 40 C. using a water bath (refluxing after foaming was observed, indicating the onset of Grignard reagent production). After initiating the reaction, the heating apparatus was removed from the reactor and the remaining 4 L of bromide was slowly added over a period of 2 hours 30 minutes while maintaining a gentle reflux of the mixture. After addition was complete, the reaction mixture was again heated to reflux (bath temperature 45 C.) for 1 hour, after which an aliquot of the reaction mixture was quenched with water and analyzed by TLC (hexane, PMA staining). This indicated complete disappearance of the starting bromide. The reaction mixture was cooled to below 10 C. using an ice bath and ethyl formateEther solution (275 mL in 4 L of ether) was added over 2 h 30 min and after addition was complete the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was cooled to 10 C., acetone (1.15 L) was slowly added to the mixture and then prepared by dissolving 7 L of ice cold water and 3.4 L of sulfuric acid with 34 L of ice cold water ) 10% sulfuric acid solution were added. The product was extracted with 3 × 10 L of ether and the combined organic layers were washed with 10 L of brine and dried over sodium sulfate (2 Kg). Concentration of the organic layer under reduced pressure gave the crude product (2 Kg) as a mixture of required dilinoleyl alcohols along with traces of O-formylated product. This crude product was redissolved in THF (4 L) and loaded into a 20 L glass reactor. To this was added a NaOH solution (0.934 Kg dissolved in 8 L of ice cold water) and the contents were heated at 65 C. for 18 h and then subjected to O-formylation by TLC (10% ether in hexane) Indicating that the product was completely converted to the desired dilinoleyl methanol. The reaction mixture was cooled, extracted with ether (3 × 4 L) and the combined organic layers were washed withWashed with 5 L of brine and dried over sodium sulfate (4 Kg). After filtration, the organic layer was concentrated to give a crude product. The crude product thus obtained was purified by column chromatography using silica gel of 60-120 mesh with 4% ether in hexane. Concentration of the pure product fractions gave pure 6 (1.45 Kg, 80%) as a colorless liquid
71.3%		To a suspension of Mg (0.897 g, 36.9 mmol) and ether (20 mL) in RB flask was added <strong>[4102-60-7]linoleyl bromide</strong> (10.0 g, 30.4 mmol) in ether (25 mL) dropwise while keeping the reaction under gentle reflux by cooling the RB flask in water. The reaction mixture was stirred at 35 C for 1 hour. To the above reaction mixture at 0 C was added ethyl formate (1.013 g, 13.68 mmol) in ether (30 mL) dropwise for 10 minutes and the reaction mixture was stirred at room temperature for 1.5 hrs. The reaction mixture was cooled in ice bath, quenched with water (30 mL), treated with 10% H2SO4 (150 mL) until the solution became homogeneous and the layer was separated. The aqueous layer was extracted with ether (200 mL x 2). The solvent was evaporated under reduced pressure to give a residue, which was re-dissolved in THF (50 mL) and 1 N NaOH (30 mL). The reaction mixture was stirred at 40 C for 5 hrs. TLC was used to monitor the reaction progress. If not complete, 1.5 g NaOH was added to the reaction mixture and the reaction mixture was continually stirred at 40 C for overnight. The reaction mixture was extracted with ether (2 x), dried over anhydrous sodium sulfate, and concentrated to give a residue, which was purified by ISCO (120 g gold silica gel cartridge) eluting with hexane to 10% EtOAc in hexane to give dilinoleyl methanol (5.16 g, 9.76 mmol, 71.3 % yield) as a colorless oil. XHNMR (500 MHz, Chloroform-d) 8 5.41-5.30 (m, 8H), 3.58 (s, 1H), 2.77 (t, J= 6.7 Hz, 4H), 2.05 (q, J= 6.9 Hz, 8H), 1.49 - 1.25 (m, 40H), 0.89 (t, J =6.8Hz, 6H).
40%		In a three-necked flask, 2.21 g of Mg and 12 ml of anhydrous ether were added. The reactor was filled with argon. 20g of product 4 dissolved in40 ml of anhydrous ether. Under argon protection, 8 ml of this solution was added dropwise to the reactor and 0.2 ml of dibromomethane was further added. The reaction solution was heated to 40C in a water bath. After the start of the reaction, the heat source was removed and the remaining 32 ml of solution was added dropwise to the reactor.The composition maintains a slight reflux condition. After completion of the addition, the reaction was heated to maintain reflux. After the reaction is completed,Reaction solutionIce bath cooling below 10C and ethyl formate in diethyl ether (2.2 ml in 32 ml diethyl ether) was added slowly. After addingAfterwards, the reaction was overnight at room temperature. Then 56 ml of ice water and 10% sulfuric acid solution were added, the organic phase was separated and the aqueous phase was extracted with ether.The organic phases are combined, washed with brine and dried over sodium sulfate. Filter and concentrate the organic phase to remove the organic solvent to obtain the crude product (alcohol and AAcid ester mixture) 16g. The crude product was dissolved with 100 ml THF, NaOH solution (7.5 g dissolved in 150 ml water) was added and heated to 65C.The reaction was 18 hours. After the reaction was completed, the reaction was cooled to room temperature and extracted with ether. The organic phases were combined and washed with 40 ml of brine.Di. Dry over sodium sulfate. Filter and concentrate the organic phase. The crude product was purified with 60-120 mesh silica gel (4% ether/n-hexane) to give pure product.DLM6a (11.6 g) (yield 40%).
	In water;	Synthesis of Dilinoleyl Methanol (III) To a suspension of Mg turnings (0.45 g, 18.7 mmol) with one crystal of iodine in 200 mL of anhydrous ether under nitrogen was added a solution of <strong>[4102-60-7]linoleyl bromide</strong> (II) in 50 mL of anhydrous ether at room temperature. The resulting mixture was refluxed under nitrogen overnight. The mixture was cooled to room temperature. To the cloudy mixture under nitrogen was added dropwise at room temperature a solution of ethyl formate (0.65 g, 18.7 mmol) in 30 mL of anhydrous ether. Upon addition, the mixture was stirred at room temperature overnight (20 hours). The ether layer was washed with 10% H2SO4 aqueous solution (100 mL), water (2*100 mL), brine (150 mL), and then dried over anhydrous Na2SO4. Evaporation of the solvent gave 5.0 g of pale oil. Column chromatography on silica gel (230-400 mesh, 300 mL) with 0-7% ether gradient in hexanes as eluent afforded two products, dilinoleyl methanol (2.0 g, III) and dilinoleylmethyl formate (1.4 g, IV).
11.6 g		2.21 g of Mg and 12 ml of anhydrous diethyl ether were added to the three-necked flask. The reactor was filled with argon. 20 g of product 4 was dissolved in 40 ml of anhydrous diethyl ether. Under argon protection, 8 ml of this solution was added dropwise to the reactor, and 0.2 ml of dibromomethane was continuously added. The reaction solution was warmed to 40 C in a water bath. After the reaction started, the heat source was removed, and the remaining 32 ml of the solution was added dropwise to the reactor, and the mixture was kept under a slight reflux. After the completion of the dropwise addition, the mixture was heated to maintain a reflux state. After completion of the reaction, the reaction solution was cooled to 10 C or less with an ice bath, and then a solution of ethyl formate in diethyl ether (2.2 ml in 32 ml of diethyl ether) was slowly added. After the completion of the dropwise addition, the reaction was allowed to proceed overnight at room temperature. Then, 56 ml of ice water and a 10% sulfuric acid solution were added, the organic phase was separated, and the aqueous phase was extracted with diethyl ether. The organic phases were combined, washed with brine and dried over sodium sulfate. Filtration and concentration of the organic phase to remove the organic solvent to obtain a crude product of 16 g (Alcohol and formate mixture). The crude product was dissolved in 100 ml of THF, NaOH solution (7.5 g dissolved in 150 ml of water) was added, and the mixture was heated to 65 C for 18 hours. After the reaction was completed, the reaction was cooled to room temperature, then it was extracted with diethyl ether and the organic phases were combined and washed with 40 ml brine. Dried over sodium sulfate. Filtrated and concentrated the organic phase. The crude product was purified with 60-120 mesh silica gel (4% diethyl ether / n-hexane) to give purified product DLM6a (11.6 g) (yield 40%).

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[2]Patent: US2013/123339,2013,A1 .Location in patent: Paragraph 0545; 0548; 0549.
[3]Patent: US2016/32320,2016,A1 .Location in patent: Paragraph 0551; 0553.
[4]Patent: JP5819291,2015,B2 .Location in patent: Paragraph 0447; 0450.
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[9]Patent: CN105085437,2018,B .Location in patent: Paragraph 0052; 0070; 0081; 0082; 0083.

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[ 4102-60-7 ]
[ 1169768-30-2 ]

References: [1]Patent: US2011/195127,2011,A1 .
[2]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[3]Patent: US9186325,2015,B2 .
[4]Patent: JP2016/84297,2016,A .
[5]Patent: US2013/123339,2013,A1 .
[6]Patent: US2016/32320,2016,A1 .

15
[ 4102-60-7 ]
[ 1169768-31-3 ]

References: [1]Patent: US2011/195127,2011,A1 .

16
[ 4102-60-7 ]
[ 1190203-55-4 ]

References: [1]Patent: US2011/195127,2011,A1 .
[2]Patent: US9186325,2015,B2 .
[3]Patent: US9186325,2015,B2 .

17
[ 4102-60-7 ]
[ 1217306-55-2 ]

References: [1]Patent: US2011/195127,2011,A1 .

18
[ 4102-60-7 ]
[ 1169768-28-8 ]

Yield	Reaction Conditions	Operation in experiment
81%		A 1 liter RBF was charged with magnesium turnings (11.1 g, 463 mmol), anhydrous THF (65 mL) and stir-bar and flushed with nitrogen. In a separate flask, a solution of <strong>[4102-60-7]linoleyl bromide</strong> (140 g, 425 mL) in anhydrous THF (1 0 mL) was prepared, and 20 mL of this solution added to the magnesium. When most of the heat had dissipated, the remainder of the bromide was added over a period of 15 minutes. Temperature was then maintained at 45C for 4 h. The reaction was then cooled (0C). Using a dropping funnel, a solution of ethyl formate (32.4 g, 438 mmol) in anhydrous THF (150 mL) was added over a 40 minute period. The reaction was stirred overnight at room temperature. The reaction was cooled to -15C and 5N HC1 (185 mL) added slowly. The mixture was transferred to a 2 L separating funnel separated. Water (150 mL) and hexane (150 mL) were added, the mixture washed, and again the aqueous removed. The organic was washed a final time with water (150 mL) and then concentrated to a yellow oil. The yellow oil was stirred with a mixture of EtOH (210 mL), water (30 mL) and KOH (15.8 g) for 1.5 h at room temp. The EtOH was evaporated and the residue treated with hexane (50 mL). 5N HC1 (200 mL) was added via dropping funnel. The organic was washed with water (2 x 50 mL) evaporated, dried and purified by chromatography (0 - 5% EtOAc in hexane, 91 g, 81%).
11.6 g		A 250 mL three-neck reactor was purged with dry argon, into which 2.21 g (92 mmol) of activated Mg and 12 mL of anhydrous diethyl ether were added. Product 4 (20 g, 61 mmol) was dissolved in anhydrous diethyl ether (40 mL). Under the protection of argon, 8 mL of the product 4 solution was added to the reactor, together with 0.2 mL (2.8 mmol) of dibromomethane. Using a water bath, the temperature of the reaction mixture was increased to 40 C. After the start of the reaction, the heating resource was removed, and the remaining solution (32 mL) was added drop wise to the reactor within 1 hour, while maintaining a gentle reflux of the mixture. After the completion of the addition, the reaction mixture was heated to keep reflux for 1 hour. After the raw materials were completely consumed, the reaction mixture was cooled to below 10 C. using an ice-bath, in which a diethyl ether solution of ethyl formate (prepared by dissolving 2.2 mL of ethyl formate in 32 mL of diethyl ether) was added slowly. The reaction mixture was warmed to room temperature and incubated for 1 hour under stirring. Then ice-cold water (56 mL) and 10% sulfuric acid solution (prepared by dissolving 27.2 mL of sulfuric acid in 272 of ice-cold water) were added, from which the organic layers were separated. The aqueous layer was extracted with diethyl ether (3×80 mL). The combined organic layers were washed with brine solution (80 ml), dried over sodium sulfate (16 g) and filtered. The organic layer was concentrated and organic solvent was removed with a vacuum pump to obtain a crude product (a mixture of alcohols and formate). This crude product was redissolved in 100 ml of THF. To this a solution of NaOH (prepared by dissolving 7.5 g of NaOH in 150 mL of water) was added and the contents were heated to and incubated at 65 C. for 18 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature and extracted with diethyl ether (3×100 mL) The combined organic layers were washed with brine solution (40 mL), dried over sodium sulfate (40 g) and filtered. The organic layer was concentrated. The thus obtained crude product was purified using a 60-120 mesh silica gel (4% ethyl ether in hexane), to obtain the pure product 6a (11.6 g, 80% yield). 1H-NMR (CDCl3, 400 MHz), delta=5.47-5.24 (m, 8H), 3.70-150 (m, 1H), 2.85-2.66 (m, 4H), 2.12-1.91 (m, 9H), 1.55-1.17 (m, 46H), 0.90-0.80 (m, 6H).

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[2]Patent: WO2011/141704,2011,A1 .Location in patent: Page/Page column 108-109.
[3]Patent: US2015/272886,2015,A1 .Location in patent: Paragraph 0039.
[4]Patent: US9186325,2015,B2 .
[5]Patent: WO2017/62862,2017,A2 .

19
[ 4102-60-7 ]
[ 1224606-06-7 ]

References: [1]Patent: WO2011/141704,2011,A1 .
[2]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[3]Patent: US2015/272886,2015,A1 .
[4]Patent: US9394234,2016,B2 .
[5]Patent: JP5819291,2015,B2 .
[6]Patent: US2013/123339,2013,A1 .
[7]Patent: US2016/32320,2016,A1 .

20
[ 4102-60-7 ]
[ 1347052-30-5 ]

References: [1]Patent: WO2011/141704,2011,A1 .
[2]Patent: US2013/123339,2013,A1 .

21
[ 924-44-7 ]
[ 4102-60-7 ]
[ 1384192-66-8 ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium; In tetrahydrofuran; diethyl ether; toluene;	Step 1: Synthesis of (6Z,9Z,29Z,32Z)-19-((9Z,12Z)-octadeca-9,12-dienyl)octatriaconta-6,9,29,32-tetraene-19,20-diol, having the following structure A 100 mL round bottom flask was charged with magnesium turnings (360 mg, 14.6 mmol) and a stir bar. The flask was dried with a heat gun for 5 minutes then cooled under nitrogen. The flask was charged with THF (5 mL) and a small grain of iodine. A solution of <strong>[4102-60-7]linoleyl bromide</strong> (4 g, 12.1 mmol) in THF (5 mL) was added slowly and after 5 minutes the reaction initiated vigorously. The solution was stirred at room temperature for 2 hours, and then ethyl glyoxalate (0.5 mL, 2.42 mmol, 50% solution in toluene) was added. The exothermic reaction was finished immediately and quenched with saturated ammonium chloride solution (5 mL). The solution diluted with water and extracted with diethyl ether (3*50 mL). The combined diethyl ether extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The oil was purified by column chromatography on silica gel 60 (eluted with 100% Hexanes to 15% Et2O in hexanes) to afford (6Z,9Z,29Z,32Z)-19-((9Z,12Z)-octadeca-9,12-dienyl)octatriaconta-6,9,29,32-tetraene-19,20-diol as a colorless oil (945 mg, 48%).

References: [1]Patent: US2012/172411,2012,A1 .

22
[ 4102-60-7 ]
[ 1384192-57-7 ]

References: [1]Patent: US2012/172411,2012,A1 .

23
[ 4102-60-7 ]
[ 1384192-59-9 ]

References: [1]Patent: US2012/172411,2012,A1 .

24
[ 4102-60-7 ]
[ 1226909-96-1 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[2]Patent: US9186325,2015,B2 .
[3]Patent: US9186325,2015,B2 .

25
[ 4102-60-7 ]
[ 1226909-74-5 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.

26
[ 4102-60-7 ]
[ 1226909-75-6 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.

27
[ 4102-60-7 ]
[ 1190203-86-1 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[2]Patent: US9701623,2017,B2 .

28
[ 4102-60-7 ]
[ 1226909-73-4 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.

29
[ 4102-60-7 ]
[ 1226909-71-2 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[2]Patent: US9186325,2015,B2 .
[3]Patent: US9186325,2015,B2 .
[4]Patent: US9186325,2015,B2 .

30
[ 4102-60-7 ]
[ 1226909-78-9 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.

31
[ 4102-60-7 ]
[ 1226909-70-1 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[2]Patent: US9186325,2015,B2 .

32
[ 4102-60-7 ]
[ 1226909-97-2 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[2]Patent: US9186325,2015,B2 .
[3]Patent: US9186325,2015,B2 .

33
[ 4102-60-7 ]
[ 1226909-98-3 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[2]Patent: US9186325,2015,B2 .
[3]Patent: US9186325,2015,B2 .

34
[ 4102-60-7 ]
[ 1226909-81-4 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[2]Patent: US9186325,2015,B2 .
[3]Patent: US9186325,2015,B2 .

35
[ 4102-60-7 ]
[ 1221271-60-8 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8529 - 8533.
[2]Patent: US9186325,2015,B2 .
[3]Patent: US9186325,2015,B2 .

Historical Records

Technical Information

• Alkyl Halide Occurrence • General Reactivity • Grignard Reaction • Heat of Combustion • Hiyama Cross-Coupling Reaction • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Dihalides • Stille Coupling • Substitution and Elimination Reactions of Alkyl Halides • Suzuki Coupling

Related Functional Groups of
[ 4102-60-7 ]

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CAS No.: 4102-60-7

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