With ethyl 2,2-dibromoacetoacetate; triphenylphosphine In dichloromethane at 20℃; for 0.25 h;
General procedure: Ethyl α,α-dibromoacetoacetate 2a (0.41 mmol, 1.2 equiv), alcohols 1a-1s (0.34 mmol, 1.0 equiv) and Ph3P (0.68 mmol, 2.0 equiv) were added under ambient temperature to 3 mL of DCE in air. After stirred at room temperature for appropriate time (monitored by TLC), the reaction was quenched by addition of H2O (3 mL) and then extracted with ethyl acetate (3×3 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silica gel with petroleum ether or mixture of petroleum ether and ethyl acetate as eluent to afford the corresponding products 3a-3s.
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 1, p. 90 - 93
[2] Chemistry and Physics of Lipids, 1993, vol. 66, # 3, p. 161 - 170
[3] JAOCS, Journal of the American Oil Chemists' Society, 1996, vol. 73, # 7, p. 847 - 850
[4] Journal of the American Pharmaceutical Association (1912-1977), vol. 38, p. 288[5] Chem.Abstr., 1949, p. 8610
[6] Bulletin de la Societe Chimique de France, 1939, vol. <5> 6, p. 1670,1674
[7] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1943, vol. 279, p. 76,83
[8] Journal of the American Chemical Society, 1947, vol. 69, p. 236
[9] Chemische Berichte, 1943, vol. 76, p. 591
[10] Journal of the Chemical Society, 1948, p. 642[11] Journal of the Chemical Society, 1934, p. 339
[12] Pr.S.Dakota Acad., 1939, vol. 19, p. 124[13] Chem.Abstr., 1940, p. 2784
[14] Helvetica Chimica Acta, 1937, vol. 20, p. 1466,1467
[15] Chemische Berichte, 1936, vol. 69, p. 1766,1769,1784
[16] Chemische Berichte, 1934, vol. 67, p. 1122
[17] Gazzetta Chimica Italiana, 1950, vol. 80, p. 180,183
[18] Journal of the American Chemical Society, 1916, vol. 38, p. 1076
[19] Tetrahedron Letters, 1978, p. 4483 - 4486
[20] Journal fuer Praktische Chemie (Leipzig), 1960, vol. 10, p. 265 - 289
[21] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1979, p. 712 - 718
[22] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 16, p. 2663 - 2665
[23] Advanced Synthesis and Catalysis, 2016, vol. 358, # 21, p. 3394 - 3413
2
[ 36653-82-4 ]
[ 2197-63-9 ]
Yield
Reaction Conditions
Operation in experiment
11%
at 80℃;
Production Example 5; Synthesis of Dicetylphosphate; To a mixture of cetyl alcohol (19.50 g, 80.4 mmol) and benzene (100 ml), phosphorus oxychloride (2.5 ml, 26.8 mmol) was added dropwise at 80° C. (solvent reflux temperature) and further stirred for 12 hours. The solvent of the reaction solution was evaporated under a reduced pressure. To the obtained residue, benzene (50 ml) was added and cooled overnight. The precipitate generated was filtrated to obtain the titled compound (white powder, 1.64 g, 3.0 mmol, yield: 11percent).1H-NMR (ppm) δ: 0.87-0.89 (t, 6H), 1.25-1.37 (br, s, 52H), 1.65-1.72 (m, 4H), 4.00-4.06 (m4H), 7.05 (br, s, 1H)13C-NMR (ppm) δ: 14.11, 22.69, 25.44, 29.18, 29.36, 29.54, 29.61, 29.66, 29.67, 29.70, 29.71, 30.16, 30.21, 31.93, 67.69, 67.7331P-NMR (ppm) δ: 2.15SIMS mass analysis:Actual measurement value; 547.85Theoretical value; 547.83, relative to (C32H68O4P)+
Reference：
[1] Patent: US2010/94020, 2010, A1, . Location in patent: Page/Page column 18
[2] Bulletin of the Chemical Society of Japan, 1978, vol. 51, p. 1877 - 1879
[3] Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 10, p. 1751 - 1754
[4] Bioconjugate Chemistry, 2010, vol. 21, # 5, p. 844 - 852
3
[ 36653-82-4 ]
[ 4697-37-4 ]
[ 2197-63-9 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 298
4
[ 36653-82-4 ]
[ 770-12-7 ]
[ 2197-63-9 ]
Reference：
[1] Journal of the Chemical Society, 1955, p. 1584,1585
5
[ 67-66-3 ]
[ 36653-82-4 ]
[ 4697-37-4 ]
[ 1623-14-9 ]
[ 598-02-7 ]
[ 3539-43-3 ]
[ 2197-63-9 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 298
6
[ 36653-82-4 ]
[ 540-10-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
With sodium bromate; sulfuric acid; sodium bromide In water at 20℃; for 24 h;
General procedure: A total of 1.0 g of 1-octanol (7.69 mmol) was taken in a 50-mL round-bottomed flask, to it NaBr 0.523 g (0.66 eq.), NaBrO 3 0.383 g (0.33 eq.), and 10 mL of H 2 O [comprises the bromide and bromate in 2:1 molar ratio] were added[6f]. The reaction mixture was stirred vigorously to dissolve the contents completely. To the above reaction mixture, the aqueous H 2 SO 4 solution (0.5 eq.) was added slowly under stirring over a period of 2.5 h at room temperature (prepared by adding 0.21 mL of 98percent H 2 SO 4 to 1 mL of water). The reaction mixture was allowed to stir for up to 24 h. After the completion of reaction, the product was extracted with CH 2 Cl 2 (3 15 mL), the organic layer was dried with Na 2 SO 4 and removal of the solvent obtained octyloctanoate in 98percent yield (0.953 g) as colorless liquid. The product was confirmed by GC–MS as well as by NMR.
With tungsten oxide impregnated Zr incorporated mesoporous silica SBA-15 In 1,3,5-trimethyl-benzene at 162℃; for 6 h; Inert atmosphere; Dean-Stark
Cetyl alcohol (CA) and palmitic acid (PA) esterification reactions were performed under N2 atmosphere in a four necked round bot-tom flask (250 ml) equipped with a Teflon coated magnetic stirring bar with a stirring rate of 520 rpm and a Dean Stark apparatus surmounted with a reflux condenser. In a typical experiment, 160 mgof catalyst was added into 25 ml of mesitylene and heated up to reaction temperature of 162 C. An equimolar solution of palmitic acid and cetyl alcohol (6 mmol) in 15 ml of mesitylene at room temperature was added into the reactor. All the reactions were carried out for a reaction time of 6 h. In a preliminary set of experiments (Table 1) it was found that the reaction was not controlled by external diffusion at 520 rpm. Samples taken at regular intervals were analyzed by Agilent 6890 gas chromatography using Ultra 1(25 m × 0.3 mm) capillary column equipped with FID. The injector temperature was 280C and the detector temperature was 320 C.The GC oven temperature was changed from 50C at 12C/min to 300C where it was kept for 35 min. Helium was used as the car-rier gas at a flow rate of 37.3 ml/min The split ratio was 24.9:1. Conversion of cetyl alcohol (CA), yield of cetyl palmitate (CP) and the selectivity to CP were defined as below. Conversion(percent)= (CAin −CAout )CAin×100 Yield(percent)= CPoutCAin×100 Selectivity to CP(percent) = CPout(CAin −CAout )×100
Reference：
[1] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1922, vol. 119, p. 282
[2] Bulletin de la Societe Chimique de France, 1947, p. 322
[3] Journal of the American Chemical Society, 1951, vol. 73, p. 5406,5407
[4] J. Appl. Chem. USSR (Engl. Transl.), 1968, vol. 41, p. 2371 - 2376[5] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1968, vol. 41, p. 2517 - 2523
Reference：
[1] Bulletin of the Chemical Society of Japan, 2005, vol. 78, # 8, p. 1558 - 1564
[2] Chemistry and Physics of Lipids, 2001, vol. 109, # 2, p. 203 - 207
[3] Die Pharmazie, 1982, vol. 37, # 10, p. 706 - 708
[4] Pharmaceutica Acta Helvetiae, 1958, vol. 33, p. 349,350
19
[ 36653-82-4 ]
[ 55357-38-5 ]
[ 58066-85-6 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2009, vol. 44, # 12, p. 4970 - 4977
With phosphoric acid; In hexane; water; for 8.5h;Heating / reflux;Product distribution / selectivity;
Experiment A.-Hexane Solvent; Myristic acid/palmitic acid, 200 cc. of 85% phosphoric acid and 1800 ml. of hexane were mixed, heated to reflux and then 251 grams of cetyl alcohol added in 30 min. The mixture was refluxed further for 8 hours. Then the hot mixture consisted of a muddy acid layer and a opaque solvent layer which could not be separated by decantation or filtration. The mixture was further diluted with three volumes of hexane causing the slushy hexane layer to further soften enough to be separated from aqueous layer. The hexane layer was then cooled to bring about crystallization of fatty ester. The weight of cetyl myristate isolated was 294 grams which had a melting point of 54-59 C. The conversion, based on the cetyl alcohol used, was 63.71%
With phosphoric acid; In n-heptane; water; for 18.0h;Heating / reflux;Product distribution / selectivity;
Experiment B.-Heptane Solvent; Myristic acid/palmitic acid, 200 cc. of phosphoric acid, and 1800 ml. of heptane were mixed, heated to reflux and then 251 grams of cetyl alcohol refluxed further for 18 hours and separated as in example A. On crystallization, the cetyl myristate obtained was much darker in colour then in Experiment-A. [0030] It is evident that this process as exemplified by Experiment B is even less satisfactory than that set forth in Experiment-A
With phosphoric acid; In water; toluene; at 92℃; for 38.5h;Heating / reflux;Product distribution / selectivity;
EXAMPLE 1; Toluene Solvent; 1800 cc. of toluene, myristic acid/palmitic acid and 400 cc. of 85% phosphoric acid were mixed, heated to 92 C. and 251 grams of cetyl alcohol was introduced over a 30-minute period. When the addition was complete, the reaction mixture was further refluxed for 38 hours. The hot reaction mixture was a two phase system consisting of a toluene layer and an aqueous phosphoric acid layer. No solid material was present. The hot toluene layer was separated and mixed with charcoal to remove the undesired colouring matter. [0037] The filtrate was cooled to bring about crystallization of cetyl myristate which was isolated by filtration. The weight of cetyl myristate isolated was 436 grams which had a melting point of 54-58 C. The percentage conversion based on the cetyl alcohol employed was 92.3 percent
With phosphoric acid; In water; xylene; at 105℃; for 1.0h;Product distribution / selectivity;
EXAMPLE 2; Xylene Solvent; Myristic acid/palmitic acid, 250 grams of 85% phosphoric acid and 1000 cc. of xylene were mixed in a three neck flask provided with thermometer, agitator and reflux condenser. The temperature was increased to 105 with good agitation and 55 grams of cetyl alcohol was introduced over a one-hour period. After the reaction the supernatant xylene layer was drawn off, and the lower phosphoric acid layer was preserved for use in the following run. [0040] The xylene layer on cooling deposited a crystalline solid which weighed 154 gms. This material consisted of cetyl myristate and any unreacted fatty acid. The crude product was easily purified by recrystallization from hot xylene to yield pure cetyl myristate M.P.=54-56 C; EXAMPLE 3; Xylene Solvent; Myristic acid/palmitic acid, 400 cc. of 85% phosphoric acid and 2400 cc. of xylene were mixed in a three neck flask provided with a thermometer, agitator and reflux condenser. The temperature was raised to 105 C. with good agitation and 251 grams of cetyl alcohol was introduced with good agitation over a 1-hour period. The mixture reflux for 36 hour. Next, the supernatant xylene layer was drawn off, and the lower phosphoric acid layer was preserved for use in a subsequent run. The xylene layer on cooling deposited a crystalline solid which weighed 438 grams. This crude material was substantially cetyl myristate and was purified by recrystallization from hot xylene so as to yield pure cetyl myristate having a melting point of 54-56 C. [0045] The water which is formed by the employment of cetyl alcohol in the course of the reaction as in Example 2 dilutes the reaction mixture but can be readily removed by azeotropic distillation of the reaction mixture
With phosphoric acid; In water; at 95℃; for 0.5h;Product distribution / selectivity;
Experiment C.-Alkylation in Absence of a Solvent; Myristic acid/palmitic acid, 400 cc. of 85% phosphoric acid were mixed, heated to 95 C., and 251 grams of cetyl alcohol was added over a period of 30 minutes. The mixture further heated in vacuum and then on cooling. The reaction mixture, which contained a finely divided white solid, was diluted to 3000 ml. with water cooled to 25 C. and filtered. The white product was treated with hot water, and the mixture filtered hot to remove any alcohol. [0033] The unreacted fatty acid was present in a large quantity. The reaction was not complete
BOC protected lysine (6.25 g, 0.018 mole) was dissolved in about 40 mL of tetrahydrofuran under a nitrogen atmosphere. The solution was cooled to about 0 C. using an ice-water bath and carbonyl diimidazole (2.93 g, 0.018 mole) was added to the cooled solution. The reaction mixture was then allowed to stir for about 5 min. at about 5 C. and then for about 30 min. at room temperature. To the resulting solution was then added by dropwise addition a solution of hexadecanol (4.38 g, 0.018 mole) in about 10 mL of tetrahydrofuran. The resulting solution was then warmed to about 45 C. and allowed to stir for about 12 h. After stirring, the solvent was evaporated under reduced pressure; the resulting residue dissolved in ethyl acetate; the ethyl acetate washed with 0.1 N hydrochloric acid (3 times), saturated aqueous sodium hydrogen carbonate (3 times), and brine (3 times); and the organic phase dried (Na2SO4). The ethyl acetate was then removed under reduced pressure to provide crude BOC protected lysine hexadecanoate that was purified using silica gel column chromatography eluted with 0 to 20 percent ethyl acetate in hexane. The solvent was then evaporated under reduced pressure to provide purified BOC protected lysine hexadecanoate. Trifluoroacetic acid (20 mL) was added to the purified BOC protected lysine hexadecanoate and the resulting reaction mixture stirred for about 5 h. Excess trifluoroacetic acid was removed under reduced pressure. The resulting residue was then dissolved in methanol and passed through a Dowex 550A(OH) resin (50 g) (commercially available from Dow Chemical Company of Midland Mich.) and the solvent removed under reduced pressure to provide lysine hexadecanoate that was dried under vacuum to provide dried lysine hexadecanoate (3.6 g).
Lysine hexadecanoate: BOC protected lysine (6.25 g, 0.018 mole) was dissolved in about 40 mL of tetrahydrofuran under a nitrogen atmosphere. The solution was cooled to about 0 C. using an ice-water bath and carbonyl diimidazole (2.93 g, 0.018 mole) was added to the cooled solution. The reaction mixture was then allowed to stir for about 5 min. at about 5 C. and then for about 30 min. at room temperature. To the resulting solution was then added by dropwise addition a solution of hexadecanol (4.38 g, 0.018 mole) in about 10 mL of tetrahydrofuran. The resulting solution was then warmed to about 45 C. and allowed to stir for about 12 h. After stirring, the solvent was evaporated under reduced pressure; the resulting residue dissolved in ethyl acetate; the ethyl acetate washed with 0.1 N hydrochloric acid (3 times), saturated aqueous sodium hydrogen carbonate (3 times), and brine (3 times); and the organic phase dried (Na2SO4). The ethyl acetate was then removed under reduced pressure to provide crude BOC protected lysine hexadecanoate that was purified using silica gel column chromatography eluted with 0 to 20 percent ethyl acetate in hexane. The solvent was then evaporated under reduced pressure to provide purified BOC protected lysine hexadecanoate. Trifluoroacetic acid (20 mL) was added to the purified BOC protected lysine hexadecanoate and the resulting reaction mixture stirred for about 5 h. Excess trifluoroacetic acid was removed under reduced pressure. The resulting residue was then dissolved in methanol and passed through a Dowex 550A(OH) resin (50 g) (commercially available from Dow Chemical Company of Midland Mich.) and the solvent removed under reduced pressure to provide lysine hexadecanoate that was dried under vacuum to provide dried lysine hexadecanoate (3.6 g).
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