[ CAS No. 6217-54-5 ]

Name: 6217-54-5|Docosahexaenoic Acid|95%
Brand: Ambeed
SKU: A267106
Rating: 94 (25 reviews)

{[proInfo.proName]} (Synonyms:Cervonic Acid; DHA) ,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

2D 3D

Structure of 6217-54-5 * Storage: {[proInfo.prStorage]}

Cart0 Bulk Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 88K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 6217-54-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 6217-54-5 ]

SDS

Alternatived Products of [ 6217-54-5 ]

Product Details of [ 6217-54-5 ]

CAS No. :	6217-54-5	MDL No. :	MFCD00065722
Formula :	C₂₂H₃₂O₂	Boiling Point :	446.732°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	328.49 g/mol	Pubchem ID :	-
Synonyms :

Safety of [ 6217-54-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P210-P261-P264-P271-P273-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501	UN#:	N/A
Hazard Statements:	H227-H315-H319-H335-H413	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 6217-54-5 ]

Upstream synthesis route of [ 6217-54-5 ]
Downstream synthetic route of [ 6217-54-5 ]

[ 6217-54-5 ] Synthesis Path-Upstream 1~2

1
[ 6217-54-5 ]
[ 89-84-9 ]
[ 1139-83-9 ]
[ 480-66-0 ]
[ 1143-70-0 ]
[ 118-93-4 ]

Reference： [1] Patent: US2005/282781, 2005, A1, . Location in patent: Page/Page column 10

2
[ 6217-54-5 ]
[ 89-84-9 ]
[ 1139-83-9 ]
[ 480-66-0 ]
[ 1143-70-0 ]
[ 118-93-4 ]

Reference： [1] Patent: US2005/282781, 2005, A1, . Location in patent: Page/Page column 10

[ 6217-54-5 ] Synthesis Path-Downstream 1~24

1
[ 6217-54-5 ]
[ 78144-19-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogen iodide; iodine; potassium hydrogencarbonate; In ethanol; at 0 - 4℃; for 18h;Inert atmosphere; Darkness;	A mixture of DHA ethyl ester (10.02 g, 28 mmol) and LiOH.H2O (5.8 g, 140 mmol) in EtOH-H2O (1:1) (60 mL) was left stirring until all the DHA ethyl ester was converted (TLC, CH2Cl2). Water (90 mL) were added, the reaction flask was covered with aluminium-foil and cooled to 0 C. Hydrogen iodide (57%; 20 mL) was added to the reaction mixture, followed successively by saturated KHCO3 (10 mL) and dropwise addition of a solution of I2 (21.32 g, 84 mmol) in EtOH (70 mL). The mixture was left stirring at 0-4 C in the dark for 18 h. The reaction was quenched by adding a saturated aq. solution of Na2S2O3 (100 mL). Solid NaCl was added to saturation and the product extracted with hexane (3 × 50 mL). The extract was washed with brine (2 × 50 mL), dried (Na2SO4) and evaporated under reduced pressure to give 8 (12.3 g; 97%) as pale yellow oil. Spectral data were in agreement with those previously reported [17].
96%	With 2,6-dimethylpyridine; iodine; In dichloromethane; at 0℃; for 15h;Inert atmosphere; Cooling with ice;	General procedure: Prepared according to literature procedure by Ulven and coworkers.27 A solution of 2,6-lutidine (2.00 equiv.) in CH2Cl2 (18.0 mL/g2,6-lutidine) was added dropwise to the acid (1.00 equiv.) and thencooled to 0 C under an argon atmosphere. An ice cold solution of I2(2.00 equiv.) in CH2Cl2 (final concentration of 70.0 mM) was added andthe stirring was continued overnight (15 h) at 0 C. The reaction wasquenched by the addition of aqueous Na2S2O3 and extracted with ethylacetate (3×). The combined organic layers were washed with saturatedaqueous NaH2PO4 (3×), brine and dried (Na2SO4). The solvent wasremoved in vacuo and the product was passed through a short silicaplug (heptane/EtOAc 1:1) to afford the iodolactone.

Reference： [1]Molecules,2014,vol. 19,p. 3804 - 3812
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3580 - 3587
[3]Acta Chemica Scandinavica,1999,vol. 53,p. 436 - 445
[4]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 98 - 108
[5]Phytochemistry,1992,vol. 31,p. 2401 - 2404
[6]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 517 - 522
[7]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 4390 - 4401
[8]Patent: WO2019/219758,2019,A1 .Location in patent: Page/Page column 36-37

2
[ 6217-54-5 ]
[ 555-43-1 ]
1-docosahexaenoyl-2,3-distearylglycerol [ No CAS ]

Reference： [1]Journal of the American Oil Chemists' Society,2000,vol. 77,p. 1139 - 1145

3
[ 6217-54-5 ]
[ 33069-62-4 ]
[3H]-Docosahexaenoic acid-Paclitaxel [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1 - 2h;	The second generation taxoids bearing different C-2, C-10, C-3'moieties were synthesized in good to excellent yields starting from 10-deacetylbaccatin III. Coupling of taxoids with DHA was carried out under standard conditions (DIC, DMAP) to give the corresponding conjugates in good yields. The reaction (see reaction A and Table A) takes place at the C-2'OH group.

Reference： [1]Patent: WO2005/41881,2005,A2 .Location in patent: Page/Page column 18-19
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 974 - 977

4
[ 6217-54-5 ]
[ 304897-49-2 ]
[ 656233-40-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile;	Example 2 Synthesis of Compound 5 tert-Butyl 4-[4-(cis-4,7,10,13,16,19-docosahexenoyl)amino]benzyl-1-piperazinecarboxylate (5). To compound 3 (0.68 g, 2.1 mmol) in ethyl acetate (100 mL) was added 10% Pd/C (0.1 g), and the reaction mixture was hydrogenated for 2 h under a pressure of 60 lb/inch2. The product was filtered, and solvent was removed in vacuo to afford amine 4 (0.6 g, 97% yield). Without further purification, to amine 4 (0.6 g, 2.06 mmol) dissolved in acetonitrile (90 mL) was added cis-4,7,10,13,16,19-docosahexenoic acid (DHA, 0.67 g, 2.0 mmol), 2-(1-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 0.94 g, 2.5 mmol), and N,N-diisopropylethylamine (2.1 mL). The reaction mixture was stirred overnight. Solvent was removed in vacuo, and the product was purified by column chromatography, eluding with ethyl acetate to afford 5 as an oil (0.91 g, 73% yield). 1H NMR (DMSO-d6): 9.84 (s, 1H, NH), 7.53-7.51 (d, 2H, J=8.80 Hz, Ar-H), 7.19-7.17 (d, 2H, J=8.40 Hz, Ar-H), 5.35-5.31 (m, 12H, CH=CH), 3.40 (s, 2H, CH2), 3.29 (brs, 4H, 2CH2), 2.83-2.75 (m, 10H, 5CH2), 2.35 (brs, 4H, 2CH2), 2.27 (t, 4H, J=4.80 Hz, 2CH2), 2.04-2.00 (m, 2H, CH2), 1.38 (s, 9H, 3*CH3), 0.91 (t, 3H, J=7.20 Hz, CH3). Anal. (C38H55N3O3.4.1H2O) C, H, N

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 5592 - 5599
[2]Patent: US2004/34033,2004,A1 .Location in patent: Page/Page column 12; Sheet 1

5
[ 6217-54-5 ]
[ 794458-06-3 ]
R(-)-N-ethyl-11-(cis-4,7,13,16,19-docosahexaenoyloxy)noraporphine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With dicyclohexyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 4h;	Example 14. General procedure for the synthesis of R (-)-N-alkyl-11- hydroxyaporphine esters (compounds 16-19). The appropriate 11-hydroxy-N-alkylnoraporphine (0.5 mmol), the corresponding acid (0.6 mmol) and a catalytic amount of 4- dimethylaminopyridine (DMAP) were dissolved in anhydrous dichloromethane (20 mL) under nitrogen. To the stirred mixture a solution of N,N'- dicyclohexylcarbodiimide (130 mg, 0.6mmol) in anhydrous dichloromethane (6 mL) was added at room temperature. After 4 hours stirring at room temperature the reaction mixture was filtered and evaporated to dryness. The crude oily product was purified by means of column chromatography (5:2 (vols) hexane: ethyl acetate) to obtain pure oily product. Example 15. Characterization of R( )-11-O-docosahexaehoyl-N ethyl- noraporphine (compound 16). Starting from N-ethyl-11-hydroxynoraporphine (14) and cis- 4,7,10,13,16,19-<strong>[6217-54-5]docosahexaenoic acid</strong> (DHA) the product is a syrupy oil (180 mg, 63%). 'H NMR (CDC13) 5 0.97 (3H, t, CH3), 1.16 (3H, t, CH3), 2.07 (2H, m, C-H), 2.3-2.7 (8H, m, C-H), 2.7-3.0 (10H, s, C-H), 3.0-3.3 (4H, m, C-H), 3 .48 (1H, m, C-H) 5.37 (12H, s, =C-H), 7.0 (1H, d, J9,10=8 Hz, H-10), 7.07 (lH, d, J8,9=8 Hz, H-8), 7.14-7.28 (3H, m, H-2, H-3, H-9), 7.74 (lH, d, J1,2=8 Hz, H- 1), Anal. (C40H49NO2) Calcd: C 83.43, H 8.58, N 2.43, Found: C 83.22, H 8.60, N 2.43, HPLC: 97.5% purity.

Reference： [1]Patent: WO2005/99702,2005,A2 .Location in patent: Page/Page column 31-32

6
[ 6217-54-5 ]
[ 121818-29-9 ]

Yield	Reaction Conditions	Operation in experiment
80%		Iodine (32.01 g, 126.13 mmol, 7.9 eq) was dissolved in THF (200 mL). A solution of KI (20.99 g, 126.42 mmol, 7.9 eq) and KHCO3 (12.82 g, 128.03 mmol, 8 eq) in water (200 mL) was added. Finally, a solution of <strong>[6217-54-5]docosahexaenoic acid</strong> (5.24 g, 15.95 mmol, 1 eq) in THF (100 mL) was added and the reaction mixture was stirred at r.t. for 22 h. Then 10% aq. Na2S2O3 (500 mL) was added, and the reaction mixture was extracted with Et2O (4 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried (MgSO4) and evaporated to give a dark orange oil (6.99 g). The dark orange oil was dissolved in MeOH (100 mL), K2CO3 (7.07 g, 15.14 mmol, 3.2 eq) was added and the mixture was stirred for 3h at r.t. Water (200 mL) and brine (200 mL) were added, and the product was extracted with Et2O (3 x 100 mL). The combined organic layers were washed with water (2 x 30 mL) and brine (30 mL). The organic phase was dried over MgSO4 and evaporated to give 4.56 g (80%) of the epoxide 6. Rf = 0.46 (30% EtOAc in hexane). 1H NMR (300 MHz, CDCl3) delta 5.64 - 5.21 (m, 10H), 3.69 (s, 3H), 3.05 - 2.92 (m, 2H), 2.91 - 2.74 (m, 8H), 2.55 - 2.47 (m, 2H), 2.47 - 2.36 (m, 1H), 2.31 - 2.18 (m, 1H), 2.15 - 2.01 (m, 2H), 2.00 - 1.88 (m, 1H), 1.87 - 1.73 (m, 1H), 0.97 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) delta 173.33, 132.18, 130.82, 128.74, 128.64, 128.50, 128.09, 127.96, 127.85, 127.13, 124.33, 56.77, 56.10, 51.88, 31.14, 26.35, 25.96, 25.79, 25.77, 25.69, 23.49, 20.70, 14.41.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 5837 - 5839
[2]Phytochemistry,1992,vol. 31,p. 2401 - 2404
[3]Tetrahedron Letters,1992,vol. 33,p. 1475 - 1478
[4]Patent: WO2019/219758,2019,A1

7
[ 6217-54-5 ]
[ 901116-76-5 ]

Yield	Reaction Conditions	Operation in experiment
		For scale-up production of diHDHA products, human recombinant cyclooxygenase-2 (COX-2) was expressed in insect Sf9 cells and isolated microsomal fractions were prepared and suspended in Tris Buffer [(100MM,] pH 8.0). Aspirin was added (2mM) (30min, RT) to assess 17R HDHA formation from DHA (lOuM) before large scale preparations that was confirmed as by LC-MS-MS analysis as in Figure 2 (see specification). Next, DHA [(100MG] from Sigma D-2534) was suspended in [ETOH] and added at 1% v/v to Borate buffer [(0.] [LMM] H3 [B03,] pH 8.5) and vortexed in a round-bottom flask (5 to 10 min under a stream of nitrogen) to form micelle suspensions (optical density > 650nm) to react first with the acetylated [-COX-2] (60 min, RT) to generate the 17R oxygenation (see illustration scheme A).
	With cyclooxygenase-II; aspirin; In ethanol;tris buffer; borate buffer;	Biogenic Synthesis of Natural Resolvins and Analogs Biogenic Synthesis of 17 R-containing HDHA products: For scale-up production of diHDHA products, human recombinant cyclooxygenase-2 (COX-2) was expressed in insect Sf9 cells and isolated microsomal fractions were prepared and suspended in Tris Buffer (100mM, pH 8.0). Aspirin was added (2mM) (30min, RT) to assess 17R HDHA formation from DHA (lOuM) before large scale preparations that was confirmed as by LC- MS-MS analysis as in Figure 2 (see specification). Next, DHA (100mg from Sigma D-2534) was suspended in EtOH and added at 1% v/v to Borate buffer (0. lmM H3 B03, pH 8. 5) and vortexed in a round-bottom flask (5 to 10 min under a stream of nitrogen) to form micelle suspensions (optical density > 650nm) to react first with the acetylated-COX-2 (60 min, RT) to generate the 17R oxygenation (see illustration scheme A). These reaction mixtures were immediately transferred and spun through a Millipore YM-30 centrifuge column for 20 min, RT. Next, isolated potato 5-lipoxygenase purchased from Cayman Chemical was added at 400ul (in accordance with each preparation's specific enzymatic activity) to 10ml reactions for 30min, 4 C in a round-bottom flask flushed with 02 rotating in an ice water bath. At time intervals, samples were taken from the reactions to monitor product formation using LC- MS-MS with tandem UV spectra recorded online with a PDA detector with a MeOH : H20 mobile phase and linear gradient. Next, the 4 position and 7 position hydroperoxy adducts respectively introduced into the 17RHDHA substrate by the actions of the 5-lipoxygenase were reduced as a mixture with the addition of solid grains of sodium borohydride (5min, RT) and the incubations were stopped with the addition of 2 vol cold MeOH. The diHDHA products were extracted using liquid-liquid acidic ether (pH 3.5) and washed to approximately neutral pH with water. The structures of the 4S, 17R and 7S, 17R-diHDHA positional isomers were established by LC-MS-MS (using conditions cited in the specification). These compounds were well resolved in rp-HPLC using MeOH: H20 (65: 35 v/v) for isolation and biologic actions.
	With boric acid; aspirin;cyclooxygenase-2; In ethanol; water; at 20℃; for 1h;pH 8.5;1% v/v to Borate buffer;	For scale-up production of diHDHA products, human recombinant cyclooxygenase-2 (COX-2) was expressed in insect Sf9 cells and isolated microsomal fractions were prepared and suspended in Tris Buffer (100mM,pH 8.0). Aspirin was added (2mM) (30min , RT) to assess 17R HDHA formation from DHA(IOuM) before large scale preparations that was confirmed as by LC- MS-MS analysis. Next, DHA (lOOmg from Sigma D-2534) was suspended in EtOH and added at 1% v/v to Borate buffer (O.lmM H3 BO3, pH 8.5) and vortexed in a round-bottom flask (5 to 10 min under a stream of nitrogen) to form micelle suspensions (optical density > 650nm) to react first with the acetylated - COX-2 (60 min, RT) to generate the 17R oxygenation (see illustration scheme A).These reaction mixtures were immediately transferred and spun through a Millipore YM-30 centrifuge column for 20 min, RT. Next, isolated potato 5- lipoxygenase purchased from Cayman Chemical was added at 400ul (in accordance with each preparation's specific enzymatic activity) to 10ml reactions for 30min, 4 C in a round-bottom flask flushed with O2 rotating in an ice water EPO <DP n="107"/>bath. At time intervals, samples were taken from the reactions to monitor product formation using LC-MS-MS with tandem UV spectra recorded online with a PDA detector with a MeOH :H2O mobile phase and linear gradient.Next, the 4 position and 7 position hydroperoxy adducts respectively introduced into the 17RHDHA substrate by the actions of the 5-lipoxygenase were reduced as a mixture with the addition of solid grains of sodium borohydride (5min, RT) and the incubations were stopped with the addition of 2 vol cold MeOH. The diHDHA products were extracted using liquid-liquid acidic ether (pH 3.5) and washed to approximately neutral pH with water. The structures of the 4S,17R and 7S,17R-diHDHA positional isomers were established by LC-MS-MS (using conditions cited in the specification). These compounds were well resolved in rp-HPLC using Me0H:H20 (65:35 v/v) for isolation and biologic actions.

Reference： [1]Patent: WO2004/14835,2004,A2 .Location in patent: Page 98-99
[2]Patent: WO2005/89744,2005,A2 .Location in patent: Page/Page column 79-81; 117; 14/31; 17/31; 20/31
[3]Patent: WO2006/78457,2006,A2 .Location in patent: Page/Page column 105-107; 112-113

8
[ 6217-54-5 ]
[ 89-84-9 ]
[ 1139-83-9 ]
[ 480-66-0 ]
[ 1143-70-0 ]
[ 118-93-4 ]

Yield	Reaction Conditions	Operation in experiment
		Eicosapentaenoic acid (EPA, 10.4 mg, Aldrich, Mlw, USA) was taken in methanol (5 ml), and the mixture was kept at ordinary temperature (25+/-2 C.) for 7 days. EPA did not exhibit the presence of any detectable amount of DBPs (1 and 2, Scheme-II) at the onset of the reaction (beginning of day-1). After autooxidation for 7 days, the products were subjected to GC-MS analysis, as the trimethylsilyl (TMS) derivatives. A small portion of the transformed product of EPA (ca. 3 mg) was dissolved in chloroform-methanol (2:1, 5 ml). An aliquot (10 mul) of this solution was treated with N,O-bis (trimethylsilyl)-trifluoroacetamide (Wako) at 60 C. for 1 hour. A portion of the silyl derivatives was injected into the GC-MS assembly. The presence of 3,8-dihydroxy-dibenzo-alpha-pyrone and benzoic acid as TMS derivatives, in the mixture was detected (FIG. 1). Analysis of the product on day-2 showed the presence of 3-hydroxy-dibenzo-alpha-pyrone (C-13) and benzoic acid (C-7) in the mixture. Among the 20-C units of EPA, DBPs comprise 13-carbons and the remaining 7-carbons constitute benzoic acid. The yield of DBPs was appreciably increased (FIG. 1) when catalytic amount of ferrous sulphate (0.1 mg) was added to the autooxidation mixture. The autooxidation of DHA was also studied similarly, when both 3-hydroxy- and 3,8-dihydroxy-dibenzo-alpha-pyrones (1 and 2, Scheme-II) were detected in the transformed products (monitored on day-2 to day-7). The remaining 9-carbons (C-22-C-13) of DHA, constituted hydroxyacetophenones (strs. 7-9, Scheme-II), which were also detected in the autooxidation mixture as their trimethylsilyl derivatives by GC-MS analysis.

Reference： [1]Patent: US2005/282781,2005,A1 .Location in patent: Page/Page column 10

9
[ 6217-54-5 ]
[ 178250-30-1 ]
[ 851309-49-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	To a solution of 3'-dephenyl-10- (methoxycarbonyl)-3'- (2-methyl-2-propyl)-2'-docosahexaenoyl- docetaxel (SB-T-1107) (63.9 mg, 75 pLmol) in dichloromethane (3.5 mL) under argon were added 4-dimethylaminopyridine (9 mg; 75 mol), 1,3-dicyclohexylcarbodiimide (19 mg; 150 pmol), and DHA (27 mg; 83 mol). The reaction mixture was stirred at ambient temperature for 1 h. After dilution with dichloromethane, the reaction mixture was washed with 5% hydrochloric acid, water, and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel (ethyl acetate/hexanes = 1/3 tol/1) to give 78.5 mg (90% yield) of DHA-SB-T-1107 as white solid: mSp. 102-105 C, [a] D22-45. 0 (c 1.0, CHCl3) ; 1H NMR (400 MHz, CDCl3) 8 0.96 (m, 9 H), 1.14 (s, 3 H), 1.22 (s, 3 H), 1.30 (s, 9 H), 1.67 (m, 3 H), 1.69 (s, 3 H), 1.88 (m, 1 H), 1.96 (s, 3 H), 2.07 (m, 2 H), 2.37 (s, 3 H), 2.47 (m, 6 H), 2.55 (m, 1 H), 2.85 (m, 10 H), 3.78 (d, J = 6. 8 Hz, 1 H), 3.86 (s, 3 H), 4.19 (d, J = 8. 2 Hz, 1 H), 4.29 (d, J = 8. 2 Hz, 1 H), 4.37 (m, 1 H), 4.43 (m, 1 H), 4.60 (d, J= 9. 3 Hz, 2 H), 4.91 (s, 1 H), 4.97 (d, J = 8.0 Hz, 1 H), 5.25-5. 50 (m, 12 H), 5.66 (d, J = 7.0 Hz, 1H), 6.12 (s, 1 H), 6.20 (t, J = 8.8 Hz, 1 H), 7.47 (t, J = 8.0 HZ, 2H), 7. 59 (t, J= 8.0 Hz, 1 H), 8.11 (d, J= 8.0 Hz, 2 H); 13C NMR (CDCl3, 400 MHz) 8 9.6. 14.3, 20.6, 21.9, 22.1, 22.5, 22.6, 23.2, 24.7, 25.6, 25.7, 25.7, 25.8, 26.6, 28.2, 33.7, 35.5, 35.6, 41.4, 43.1, 45.6, 48.9, 55.5, 58.5, 71.5, 72.0, 74.4, 75.1, 76.4, 76.9, 78.3, 79.2, 79.7, 80.9, 84.4, 126.9, 127.4, 127.7, 127.8, 127. 9,128. 3,128. 3,128. 4,128. 5,128. 7,129. 2,129. 5,130. 1,130. 2,130. 2,131. 9, 133. 4,144. 2, 155. 1, 155. 6,166. 8,168. 1,169. 4,172. 1,203. 9

Reference： [1]Patent: WO2005/41881,2005,A2 .Location in patent: Page/Page column 12-13

10
[ 6217-54-5 ]
[ 255735-88-7 ]
[ 1204318-28-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine; HATU; In acetonitrile; at 0 - 20℃;	Example 21; Preparation of N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl)-2-hydroxybenzamide (14); To a solution of tert-butyl 2-aminopropylcarbamate (1.06 g, 6.09 mmol, prepared as previously described), DHA (2.0 g, 6.09 mmol) and Et3N (1.7 mL, 12.8 mmol) in CH3CN (40 mL) at 0° C. was added HATU (2.31 g, 6.09 mmol). The mixture was stirred (RT, 16 h) and concentrated under reduced pressure. The residue was diluted with brine (100 mL) and extracted with EA (2.x.100 mL). The combined organic layers were washed with saturated NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with EA-PE (0-25percent) to afford tert-butyl 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropylcarbamate (2.1 g, 70percent) as a light yellow oil. Mass calculated for C30H48N2O3=484.71; found: [M+H]+=485.6.

Reference： [1]Patent: US2010/41748,2010,A1 .Location in patent: Page/Page column 123

11
[ 6217-54-5 ]
[ 122734-32-1 ]
[ 1204318-24-0 ]

Yield	Reaction Conditions	Operation in experiment
77%	With triethylamine; HATU; In acetonitrile; at 20℃; for 16h;	Example 19; Preparation of 2-hydroxy-N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)benzamide (12); To a solution of <strong>[122734-32-1]tert-butyl 2-(methylamino)ethylcarbamate</strong> (0.82 g, 4.7 mmol), prepared as previously described, DHA (1.55 g, 4.7 mmol) and Et3N (1.32 mL, 9.4 mmol) in CH3CN (40 mL) was added HATU (1.79 g, 4.7 mmol). The mixture was stirred (RT, 16 h) and concentrated under reduced pressure. The residue was diluted with brine (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with saturated NaHCO3 (150 mL) and brine (150 mL), dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with EA-PE (0-50%) to afford tert-butyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethylcarbamate (1.71 g, 77%) as a light yellow oil. Mass calculated for C30H48N2O3=484.71; found: [M+H]+=485.6.

Reference： [1]Patent: US2010/41748,2010,A1 .Location in patent: Page/Page column 121

12
[ 6217-54-5 ]
[ 2934-05-6 ]
[ 1224157-47-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 1866 - 1874

13
[ 6217-54-5 ]
[ 657-24-9 ]
[ 1384513-23-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	In acetonitrile; at 20℃; for 1.08333h;Darkness;	[Amino(imino)methyl] amino}(dimethylamino)methaniminium (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate N,N-Dimethylimidodicarbonimidic diamide (968 mg, 7.61 mmol) was dissolved in acetonitrile (36 mL) and the resulting solution was filtered through a medium frit to remove a small amount of sodium chloride that precipitated. To the filtrate was added dropwise at room temperature (over a 5 minute period) a solution of (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16, 19-hexaenoic acid (2.00 g, 6.09 mmol) in acetonitrile (35 mL). A white solid precipitated immediately upon addition of the acid. The reaction flask was covered in foil to protect it from light. After stirring for 1 h at room temperature, the mixture was chilled to 0 C. for 1 h, and then filtered under an atmosphere of nitrogen. The solid was washed with 50 mL ice-cold acetonitrile and then quickly transferred to a foil-covered round bottom flask and placed under high vac. The material was left under high vacuum overnight to yield 2.54 g (91%) of 1 as a light tan solid. The material was found to be air and light sensitive, and was therefore stored in an amber vial under nitrogen: MP 124-127 C. (turned brown); 1H NMR (400 MHz, MeOD) 5.36 (m, 12 H), 3.03 (s, 6 H), 2.85 (m, 10 H), 2.37 (m, 2 H), 2.19 (m, 2 H), 2.09 (m, 2 H), 0.97 (t, J=7.57 Hz, 3 H); MS (ESI-) for C22H32O2 m/z 327.3 (M-H).
88%	With Tocopherol; In methanol; ethyl acetate; at 55℃;	0262] A solution of metformin free base (2.76 g, 21.4 mmol) in methanol (40 mL) was heated to 55C, then a solution of DHA (6.57 g, 20 mmol) in methanol (25 mL) which had been treated with alpha-D-tocopherol (120mg in 0.4 mL of ethyl acetate) was added in one portion. The mixture was stirred a few minutes more and cooled to room temperature over 20 min and concentrated in vacuo. The residue was triturated with acetonitrile (50 mL), collected and dried in vacuo at room temperature to afford 8.09 g (88%) of Metformin DHA salt as a waxy white solid. H1 NMR (400 MHz, d4 MeOH): delta 5.33-5.27 (m, 12H), 3.02 (s, 6H), 2.87-2.79 (m, 10H), 2.38-2.33 (m, 2H), 2.21-2.17 (m, 2H), 2.11-2.03 (m, 2H), 0.96 (t, 3H, J=7.5 Hz).

Reference： [1]Patent: US2012/178813,2012,A1 .Location in patent: Page/Page column 4
[2]Patent: US2017/119841,2017,A1 .Location in patent: Paragraph 0262

14
[ 6217-54-5 ]
[ 13515-95-2 ]
[ 1426335-40-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 18h;	To a suspension of L-<strong>[13515-95-2]lysine methyl ester dihydrochloride</strong> (2.33 g, 10 mmol), EDC (2.88 g, 15 mmol), HOBt (2.03 g, 15 mmol) and Et3N (3.03 g, 30 mmol) in 30 mL of CH2Cl2 was added DHA (3.12 g, 9.5 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was washed with saturated aqueous NH4Cl (330 mL) and brine (330 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (pentane/EtOAc) to afford 4.67 g of (S)-methyl 2,6-di((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)hexanoate (Yield: 60percent). 1H NMR (400 MHz, CDCl3) delta 0.95-1.01 (m, 6H), 1.26-1.40 (m, 2H), 1.48-1.55 (m, 2H), 1.65-1.73 (m, 1H), 1.79-1.85 (m, 2H), 2.03-2.13 (m, 4H), 2.19-2.24 (m, 2H), 2.27-2.32 (m, 2H), 2.37-2.45 (m, 4H), 2.80-2.85 (m, 20H), 3.20-3.27 (m, 2H), 3.74-3.75 (d, J is 2.4 Hz, 3H), 4.56-4.60 (m, 1H), 5.27-5.46 (m, 24H), 5.68 (s, 1H), 6.18-6.21 (d, J is 7.5 Hz, 1H).

Reference： [1]Patent: US2013/59801,2013,A1 .Location in patent: Paragraph 0339-0341

15
[ 68252-28-8 ]
[ 6217-54-5 ]
[ 1613318-00-5 ]

Yield	Reaction Conditions	Operation in experiment
75%		To a stirred solution of docosahexaenoic acid (1.0 eq) in DMF (10.0 vol), DIPEA(3.0 eq) and HATU(1.5 eq) were added at room temperature and stirred for 30.0 minutes, then <strong>[68252-28-8]oxiracetam</strong>, compound- 1 (1.2 eq) was added slowly to it and stirred for 2.0 hrs. Reaction was monitored by TLC. On completion of the reaction, the solvent was removed in vacuo and the crude was diluted with water and extract twice with DCM. The organic layer was washed with water followed by brine and dried over anhydrous Na2S04 and evaporated under reduced pressure to obtain the final product, compound-2 (yield: 75%). Mol. Formula: C28H40N2O4 ; Mol. Wt.: 468.63.

Reference： [1]Patent: WO2014/87367,2014,A2 .Location in patent: Paragraph 0099

16
[ 6217-54-5 ]
[ 77472-70-9 ]
[ 1613318-02-7 ]

Yield	Reaction Conditions	Operation in experiment
75%		To a stirred solution of docosahexaenoic acid (1.0 eq) in DMF (10.0 vol), DIPEA (3.0 eq) and HATU (1.5 eq) were added at room temperature and stirred for 30.0 minutes, then <strong>[77472-70-9]phenylpiracetam</strong>, compound- 1 (1.2 eq) was added slowly to it and stirred for 2.0 hrs. Reaction was monitored by TLC. On completion of the reaction, the solvent was removed in vacuo and the crude was diluted with water and extracted twice with DCM. The organic layer was washed with water followed by brine and dried over anhydrous Na2S04 and evaporated under reduced pressure to obtain final product compound -2 (yield 75%). Mol. Formula: C344N203 ; Mol. Wt.: 528.72.

Reference： [1]Patent: WO2014/87367,2014,A2 .Location in patent: Paragraph 00100

17
[ 7491-74-9 ]
[ 6217-54-5 ]
[ 1613318-03-8 ]

Yield	Reaction Conditions	Operation in experiment
75%		To a stirred solution of docosahexaenoic acid (1.0 eq) in DMF(10.0 v) , DIPEA(3.0 eq) and HATU (1.5 eq) were added at room temperature and stirred for 30.0 minutes, then <strong>[7491-74-9]piracetam</strong> compound- 1 (1.2 eq) was added slowly to it and stirred for 2.0 hrs. Reaction was monitored by TLC. On completion of the reaction, the solvent was removed in vacuo and the crude was diluted with water and extracted twice with DCM. The organic layer was washed with water followed by brine and dried over anhydrous Na2S04 and evaporated under reduced pressure to yield compound - 2 (yield 75%).

Reference： [1]Patent: WO2014/87367,2014,A2 .Location in patent: Paragraph 00101

18
[ 61278-21-5 ]
[ 81926-94-5 ]
[ 6217-54-5 ]
C₂₅H₃₉NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With Novozym 435 lipase on resin; In acetone; at 35℃; for 8h;Green chemistry; Enzymatic reaction;	General procedure: A representative synthetic procedure is given hereafter: To 500mg (1.5mmol) of DPA ethyl ester as an oil were added 100mg of Novozym 435 lipase on resin and 5 equiv (7.5mmol) of serinol. A minimum amount of acetone was then added to decrease viscosity (1mL). The mixture was magnetically stirred for 4-18h at 35C until TLC indicated complete disappearance of the ethyl ester (to be noted, LC-MS methods with UV detection are not useful to follow these reactions owing to the very low absorbance of the chromophores). The reaction was then filtered, acetone was evaporated then water added. The mixture was extracted with a minimal amount of diethyl ether (1mL) thrice. The organic phase was dried with magnesium sulfate, filtered then evaporated under reduced pressure. The crude product was purified by flash chromatography with hexane/ethyl acetate to give the desired amide 25 as a colorless oil in 60% yield (>90% purity by 1H NMR).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 5635 - 5638

19
[ 81926-94-5 ]
[ 66211-46-9 ]
[ 6217-54-5 ]
C₂₅H₃₉NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With Novozym 435 lipase on resin; In acetone; at 35℃; for 8h;Green chemistry; Enzymatic reaction;	General procedure: A representative synthetic procedure is given hereafter: To 500mg (1.5mmol) of DPA ethyl ester as an oil were added 100mg of Novozym 435 lipase on resin and 5 equiv (7.5mmol) of serinol. A minimum amount of acetone was then added to decrease viscosity (1mL). The mixture was magnetically stirred for 4-18h at 35C until TLC indicated complete disappearance of the ethyl ester (to be noted, LC-MS methods with UV detection are not useful to follow these reactions owing to the very low absorbance of the chromophores). The reaction was then filtered, acetone was evaporated then water added. The mixture was extracted with a minimal amount of diethyl ether (1mL) thrice. The organic phase was dried with magnesium sulfate, filtered then evaporated under reduced pressure. The crude product was purified by flash chromatography with hexane/ethyl acetate to give the desired amide 25 as a colorless oil in 60% yield (>90% purity by 1H NMR).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 5635 - 5638

20
[ 6217-54-5 ]
[ 402-46-0 ]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(4-fluorophenylsulfonyl)docosa-4,7,10,13,16,19-hexaenamide [ No CAS ]