* 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.
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 C32H36ClNO2P2Ru; potassium tert-butylate; hydrogen; In tetrahydrofuran; at 120℃; under 38002.6 Torr; for 20h;Autoclave; Green chemistry;
General procedure: In a glove box in a nitrogen atmosphere, 3.33 mg of ruthenium complex 1c (0.005 mmol) Add to a 125-mL Parr autoclave, After adding 11.2 mg of potassium t-butoxide (0.1 mmol), Then take 2mL of tetrahydrofuran and add it to the kettle for a while. Finally, methyl benzoate (1.3615 g, 10 mmol) was added. After the autoclave is sealed, it is taken out of the glove box. Charge hydrogen to 50 atm. The mixture in the reaction kettle was heated and stirred in an oil bath at 120 C for 10 hours, The reactor was cooled to room temperature in a water bath and the remaining gas was slowly drained from the fume hood. Tridecane (50 muL) was added to the mixture as an internal standard, and the yield of methyl benzoate was determined by gas chromatography to be 99%.
92%
With C30H34Cl2N2P2Ru; potassium methanolate; hydrogen; In tetrahydrofuran; at 100℃; under 38002.6 - 76005.1 Torr; for 15h;Glovebox; Autoclave;
General procedure: In a glove box, add a ruthenium complex Ia (0.3 to 0.7 mg, 0.0002 to 0.001 mmol) to a 300 mL autoclave,Potassium methoxide (35-700 mg, 0.5-10 mmol), tetrahydrofuran (4-60 mL), and ester compounds (10-200 mmol).After sealing the autoclave, take it out of the glove box and fill it with 50 100atm of hydrogen.The reaction kettle was heated and stirred in an oil bath at 100 C for 10 to 336 hours.After the reaction kettle was cooled in an ice-water bath for 1.5 hours, the excess hydrogen was slowly released.The solvent was removed from the reaction solution under reduced pressure, and the residue was purified with a short silica gel column to obtain an alcohol compound. The results are shown in Table 5.
sulfuric acid; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
COMPARATIVE EXAMPLE 1; This example demonstrates a typical prior art process of using a conventional acid catalyst. A reactor was charged with palmitic acid (7.79 parts), cetyl alcohol (14.71 parts) and water (6.47 parts). After warming under agitation to 70-75 C., sulphuric acid (10% aqueous solution, 1.15 parts) was added and the mixing temperature maintained for six hours. The reaction mixture was biphasic. A sample of the mixture revealed that 8.2 mole % of the palmitic acid was converted into the ester.
sulfuric acid; 1-butanesulfonic acid sodium salt; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 14-33; Experiments were conducted to study the effect of the amount and type of hydrolyzable catalyst. The reactor was charged with palmitic acid, cetyl alcohol, the sodium salt of the hydrolyzable catalyst, and water. After warming under agitation to 70-75 C., sulphuric acid is added and the mixing and temperature maintained for 6 hours. Samples of the mixture are taken to determine the mole conversion of palmitic acid into ester. The results are shown in Table 3 below:
sulfuric acid; sodium hexyl sulfate; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 14-33; Experiments were conducted to study the effect of the amount and type of hydrolyzable catalyst. The reactor was charged with palmitic acid, cetyl alcohol, the sodium salt of the hydrolyzable catalyst, and water. After warming under agitation to 70-75 C., sulphuric acid is added and the mixing and temperature maintained for 6 hours. Samples of the mixture are taken to determine the mole conversion of palmitic acid into ester. The results are shown in Table 3 below:
sulfuric acid; sodium dodecyl-sulfate; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 3-7; Experiments were conducted to determine the preferred ratio of carboxylic acid to alcohol. A reactor was charged with various amounts of palmitic acid, cetyl alcohol, sodium lauryl sulphate, (10% aqueous solution, 6.75 parts), and water (0.29 parts). After warming under agitation to 70-75 C., sulphuric acid (10% aqueous solution, 1.26 parts) was added and the mixing and temperature maintained for six hours. Samples of the reaction products were taken to determine the mole % conversion of palmitic acid into ester. The results are shown in Table 1 below:; Experiments were conducted to study the amount and type of strong acid. A reactor was charged with palmitic acid (1.56 parts), cetyl alcohol (2.94 parts), sodium lauryl sulphate (0.14 parts), and water. After warming under agitation at 70-75 C., the strong acid was added and the mixing and temperature maintained for 6 hours. Samples of the mixture were taken to determine the mole conversion of the palmitic acid into ester. The results are shown in Table 2 below:; Experiments were conducted to study the effect of the amount and type of hydrolyzable catalyst. The reactor was charged with palmitic acid, cetyl alcohol, the sodium salt of the hydrolyzable catalyst, and water. After warming under agitation to 70-75 C., sulphuric acid is added and the mixing and temperature maintained for 6 hours. Samples of the mixture are taken to determine the mole conversion of palmitic acid into ester. The results are shown in Table 3 below:
sulfuric acid; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 14-33; Experiments were conducted to study the effect of the amount and type of hydrolyzable catalyst. The reactor was charged with palmitic acid, cetyl alcohol, the sodium salt of the hydrolyzable catalyst, and water. After warming under agitation to 70-75 C., sulphuric acid is added and the mixing and temperature maintained for 6 hours. Samples of the mixture are taken to determine the mole conversion of palmitic acid into ester. The results are shown in Table 3 below:
sulfuric acid; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 14-33; Experiments were conducted to study the effect of the amount and type of hydrolyzable catalyst. The reactor was charged with palmitic acid, cetyl alcohol, the sodium salt of the hydrolyzable catalyst, and water. After warming under agitation to 70-75 C., sulphuric acid is added and the mixing and temperature maintained for 6 hours. Samples of the mixture are taken to determine the mole conversion of palmitic acid into ester. The results are shown in Table 3 below:
sulfuric acid; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 14-33; Experiments were conducted to study the effect of the amount and type of hydrolyzable catalyst. The reactor was charged with palmitic acid, cetyl alcohol, the sodium salt of the hydrolyzable catalyst, and water. After warming under agitation to 70-75 C., sulphuric acid is added and the mixing and temperature maintained for 6 hours. Samples of the mixture are taken to determine the mole conversion of palmitic acid into ester. The results are shown in Table 3 below:
sulfuric acid; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 14-33; Experiments were conducted to study the effect of the amount and type of hydrolyzable catalyst. The reactor was charged with palmitic acid, cetyl alcohol, the sodium salt of the hydrolyzable catalyst, and water. After warming under agitation to 70-75 C., sulphuric acid is added and the mixing and temperature maintained for 6 hours. Samples of the mixture are taken to determine the mole conversion of palmitic acid into ester. The results are shown in Table 3 below:
sulfuric acid; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 14-33; Experiments were conducted to study the effect of the amount and type of hydrolyzable catalyst. The reactor was charged with palmitic acid, cetyl alcohol, the sodium salt of the hydrolyzable catalyst, and water. After warming under agitation to 70-75 C., sulphuric acid is added and the mixing and temperature maintained for 6 hours. Samples of the mixture are taken to determine the mole conversion of palmitic acid into ester. The results are shown in Table 3 below:
sulfuric acid; sodium octylsulfonate; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 14-33; Experiments were conducted to study the effect of the amount and type of hydrolyzable catalyst. The reactor was charged with palmitic acid, cetyl alcohol, the sodium salt of the hydrolyzable catalyst, and water. After warming under agitation to 70-75 C., sulphuric acid is added and the mixing and temperature maintained for 6 hours. Samples of the mixture are taken to determine the mole conversion of palmitic acid into ester. The results are shown in Table 3 below:
sodium lauryl sulfate, mixed alcohol sulfates; mixture of; sulfuric acid; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 14-33; Experiments were conducted to study the effect of the amount and type of hydrolyzable catalyst. The reactor was charged with palmitic acid, cetyl alcohol, the sodium salt of the hydrolyzable catalyst, and water. After warming under agitation to 70-75 C., sulphuric acid is added and the mixing and temperature maintained for 6 hours. Samples of the mixture are taken to determine the mole conversion of palmitic acid into ester. The results are shown in Table 3 below:
With sodium dodecyl-sulfate;hydrogenchloride; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 8-13; Experiments were conducted to study the amount and type of strong acid. A reactor was charged with palmitic acid (1.56 parts), cetyl alcohol (2.94 parts), sodium lauryl sulphate (0.14 parts), and water. After warming under agitation at 70-75 C., the strong acid was added and the mixing and temperature maintained for 6 hours. Samples of the mixture were taken to determine the mole conversion of the palmitic acid into ester. The results are shown in Table 2 below:
With sodium dodecyl-sulfate;nitric acid; In water; at 70 - 75℃; for 6.0h;Product distribution / selectivity;
EXAMPLES 8-13; Experiments were conducted to study the amount and type of strong acid. A reactor was charged with palmitic acid (1.56 parts), cetyl alcohol (2.94 parts), sodium lauryl sulphate (0.14 parts), and water. After warming under agitation at 70-75 C., the strong acid was added and the mixing and temperature maintained for 6 hours. Samples of the mixture were taken to determine the mole conversion of the palmitic acid into ester. The results are shown in Table 2 below:
98.3%Chromat.
With tungsten oxide impregnated Zr incorporated mesoporous silica SBA-15; In 1,3,5-trimethyl-benzene; at 162℃; for 6.0h;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(%)= (CAin -CAout )CAin×100 Yield(%)= CPoutCAin×100 Selectivity to CP(%) = CPout(CAin -CAout )×100
With C28H60O3PS(1+)*C2F6NO4S2(1-); at 60℃; for 6.0h;Sealed tube;
General procedure: In a 15 mL vial containing a stirring bar,0.3 mmol of the ionic liquid catalyst shown in Table 11 mmol of carboxylic acid,And 1 mmol of alcohol was added.Seal the vial with a cap,Immerse the vial in a water bath or oil bath adjusted to the temperature shown in Table 1,Stir for 6 hoursCarboxylic acid and alcohol were reacted.After completion of the reaction, in all examples,The liquid phase containing the ester compound (hereinafter sometimes referred to as ?product phase?) was separated from the ionic liquid phase.
With hydroquinone; In cyclohexane; at 60 - 140℃; for 6h;
100 g of hexadecanol, 0.8 g of hydroquinone,5g in-situ acid resin was added to the round bottom flask, stirred and heated to 60 C.To completely dissolve hydroquinone, add 40 mL of cyclohexane.36.69 g of acrylic acid was added, and the temperature was raised to 120 C for two hours.The temperature was further raised to 140 C, and the reaction was completed for four hours.The resin was removed by filtration, and the filtrate was analyzed by high performance liquid chromatography.The conversion rate was 93.5%. The filtrate is washed with water and neutralized with sodium carbonate solution.Washed to neutrality and dried to give hexadecyl acrylate.The infrared spectrum of the product is shown in Figure 3,The nuclear magnetic resonance spectrum of the product is shown in Fig. 6, and the nuclear magnetic resonance spectrum of the product is shown in Fig. 7.
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
With sodium hydrogencarbonate; In diethyl ether; benzene;
Synthesis of Hexadecanylacrylate Hexadecanylacrylate was prepared by dissolving 10 g of hexadecanol in 50 ml of benzene. A 1.2 molar excess of acryloylchloride was added to the mixture and refluxed at 80 C. for 24 hours with stirring. The reaction mixture was allowed to cool to room temperature and the solvent was removed by roto-evaporation and room temperature water bath. The product was redissolved and 100 ml of diethyl ether and extracted five times with an equal volume of 10% NaHCO3 in a separatory funnel. The ether fraction was isolated and the solvent was removed by roto-evaporation at room temperature followed by vacuum drying in a room temperature oven. Hexadecanylacrylate is represented by the formula (XI): STR13
EXAMPLE 10 Preparation of 1,3-Bis(hexadecyloxy)-2-propanol using the Cascading Polyol Technique To a 500 milliliter round bottom flask equipped with an overhead stirrer, nitrogen inlet, reflux condenser, additional funnel, and temperature controller was charged 60.61 grams of hexadecanol (0.25 moles), 6.18 grams of <strong>[68-05-3]tetraethylammonium iodide</strong> (0.024 moles), 1.44 grams of water (0.082 moles), 20.20 grams of potassium hydroxide (0.36 moles), and 125 grams of toluene. To a 100 milliliter addition funnel was charged 11.10 grams of epichlorohydrin (0.12 moles) and 25 grams of toluene. The solution was brought to 65 C. at which time the epichlorohydrin solution was added over a period of 15 minutes while maintaining a reaction temperature of 65 C.+-5 C. The reaction was allowed to proceed for 48 hours. After 48 hours, the solution was cooled down to room temperature. The toluene solution was washed with two 250 milliliter portions of deionized water. The aqueous layers were drained off, and the toluene was removed using a rotary evaporator. The final yield of product was 70.9 grams which is 109% of theory (residual is hexadecanol).
With triethylamine; In tetrahydrofuran; at 0℃; for 1h;
Example 13 <n="73"/>Synthesis of 3-[2-(2-{2-[(2-Cyano-ethoxy)-hexadecyloxy-phosphoryloxy]-ethoxy}-ethoxy)- ethoxy]-propionic acid (A)5.1 g of hexadecanol was dissolved in 40 imL of tetrahydrofuran (THF) and added 4.5 imL triethylamine (TEA). The solution was cooled with ice and 5 g of 2-Cyanoethyl N,N- diisopropyl-chlorophosphoramidite was added. The mixture was stirred under nitrogen for 1 h. Then the white precipitate (triethylammonium chloride) was filtered off and washed once with THF.60 imL of 0.25M tetrazol in acetonitrile and 5 g of tert-Butyl 12-hydroxy-4,7,10- trioxadodecanoate were added and the reaction was stirred at room temperature for 5 h. 7.8 g of iodine was dissolved in 100 ml_ THF/2.6-lutidin/water 7/2/1 and added to the reaction, which was stirred then over night. <n="74"/>Natriumsulfite solution was added to the reaction mixture until the colour of iodine disappeared and the product was distracted with ethylacetate. The org. phase was washed with sat. sodiumcarbonate and sat. sodiumchloride solution.The org. phase was collected and the solvent was removed in vacuum. The oil was taken up in heptane and the solution was filtered once. The heptane was removed in vacuum.The residual oil was treated for 30 min with 30 imL dichlormethane (DCM) and 50 imL trifluoroacetic acid (TFA), after which the solvent was again removed in vacuum. The oil was taken up in DCM and washed with IN HCI. The org. phase was dried over sodiumsulfate.After removal of the solvent, the oil was purified on silica using ethylacetate with 1% acetic acid.1H-NMR (400.13 MHz, CDCI3) 0.88 (t, 3H), 1.24-1.40 (m, 26H), 1.69 (tt, 2H), 2.59 (m, 2H), 2.79 (m, 2H), 3.62-3.69 (m, 8H), 3.72-3.79 (m, 4H), 4.10 (dt, 2H), 4.18-4.36 (m, 4H).
With hydrogen;tributylphosphine; cobalt(II) decanoate; In n-heptane; at 170℃; under 63756.4 Torr; for 48h;Conversion of starting material;
Co(II)-decanoate (1.2% Co in heptane) (2.5 ml, 0.36 mmol), heptane (7 ml), C10-C15 olefins/C10-C15 paraffins (20 ml, pre-mixed each 8.3% by volume as described above) and nBu3P (1.44 mmol) were placed in a 50 ml autoclave, degassed with argon and heated to 170 C. Syngas (H2:CO 2:1) was added to 85 bar and supplied at this pressure for 48 h.Using an Agilent Pona GC-column (50 m×0.20 mm×0.50 musn, 40 C. for 5 minutes, 10 C./minute to 300 C., 300 C. for 20 minutes) which separates mainly on differential boiling points, the reaction mixture containing the C11-C16 alcohols and C10-C15 paraffins, was injected and the GC trace indicated that tridecane, tetradecane and pentadecane overlap with the resulting alcohols indicating that it would not be possible to separate all the paraffins via fractional distillation from the alcohol products (see FIG. 5).
[0184] The shampoo compositions illustrated in the following Examples illustrate specific embodiments of the shampoo compositions of the present invention, but are not intended to be limiting thereof. Other modifications can be undertaken by the skilled artisan without departing from the spirit and scope of this invention. These exemplified embodiments of the shampoo composition of the present invention provide enhanced conditioning benefits to the hair. [0185] The shampoo compositions illustrated in the following Examples are prepared by conventional formulation and mixing methods, an example of which is set forth hereinbelow. All exemplified amounts are listed as weight percents and exclude minor materials such as diluents, preservatives, color solutions, imagery ingredients, botanicals, and so forth, unless otherwise specified. [0186] The compositions illustrated in the examples were prepared in the following manner (all percentages are based on weight unless otherwise specified). [0187] For each of the compositions, 6-9% of ammonium laureth-3 sulfate, P43 oil, PureSyn6 oil, cationic polymers, 0-1.5% Ammonium Xylene Sulfonate, and 0-5% water was added to a jacketed mix tank and heated to about 74 C. with agitation to form a solution. Citric Acid, Sodium Citrate, Sodium Benzoate, Disodium EDTA, Cocamide MEA and 0.6-0.9% Cetyl alcohol, were added to the tank and allowed to disperse. Ethylene glycol distearate (EGDS) was then added to the mixing vessel, and melted. After the EGDS was well dispersed (after about 10 minutes) preservative was added and mixed into the surfactant solution. This mixture was passed through a heat exchanger where it was cooled to about 35 C. and collected in a finishing tank. As a result of this cooling step, the ethylene glycol distearate crystallized to form a crystalline network in the product. [0188] Separately about 20% of the water was heated to about 74 C. and the remainder of the Cetyl Alcohol, Stearyl Alcohol, and the Cationic Surfactant were added to it. After incorporation, this mixture was passed through a heat exchanger where it was cooled to about 35 C. As a result of this cooling step, the Fatty Alcohols and surfactant crystallized to form a crystalline gel network. [0189] These two premixes are the mixed together and the remainder of the surfactants, perfume, Dimethicone, Sodium Chloride or Ammonium Xylene Sulfonate for viscosity adjustment and the remainder of the water were added with ample agitation to insure a homogeneous mixture. [0190] Preferred viscosities range from about 5000 to about 9000 centipoise at 27 C. (as measured by a Wells-Brookfield model RVTDCP viscometer using a CP-41 cone and plate at 2/s at 3 minutes).
Yield
Reaction Conditions
Operation in experiment
EXAMPLES [0184] The shampoo compositions illustrated in the following Examples illustrate specific embodiments of the shampoo compositions of the present invention, but are not intended to be limiting thereof. Other modifications can be undertaken by the skilled artisan without departing from the spirit and scope of this invention. These exemplified embodiments of the shampoo composition of the present invention provide enhanced conditioning benefits to the hair. [0185] The shampoo compositions illustrated in the following Examples are prepared by conventional formulation and mixing methods, an example of which is set forth hereinbelow. All exemplified amounts are listed as weight percents and exclude minor materials such as diluents, preservatives, color solutions, imagery ingredients, botanicals, and so forth, unless otherwise specified. [0186] The compositions illustrated in the examples were prepared in the following manner (all percentages are based on weight unless otherwise specified). [0187] For each of the compositions, 6-9% of ammonium laureth-3 sulfate, P43 oil, PureSyn6 oil, cationic polymers, 0-1.5% Ammonium Xylene Sulfonate, and 0-5% water was added to a jacketed mix tank and heated to about 74 C. with agitation to form a solution. Citric Acid, Sodium Citrate, Sodium Benzoate, Disodium EDTA, Cocamide MEA and 0.6-0.9% Cetyl alcohol, were added to the tank and allowed to disperse. Ethylene glycol distearate (EGDS) was then added to the mixing vessel, and melted. After the EGDS was well dispersed (after about 10 minutes) preservative was added and mixed into the surfactant solution. This mixture was passed through a heat exchanger where it was cooled to about 35 C. and collected in a finishing tank. As a result of this cooling step, the ethylene glycol distearate crystallized to form a crystalline network in the product. [0188] Separately about 20% of the water was heated to about 74 C. and the remainder of the Cetyl Alcohol, Stearyl Alcohol, and the Cationic Surfactant were added to it. After incorporation, this mixture was passed through a heat exchanger where it was cooled to about 35 C. As a result of this cooling step, the Fatty Alcohols and surfactant crystallized to form a crystalline gel network. [0189] These two premixes are the mixed together and the remainder of the surfactants, perfume, Dimethicone, Sodium Chloride or Ammonium Xylene Sulfonate for viscosity adjustment and the remainder of the water were added with ample agitation to insure a homogeneous mixture. [0190] Preferred viscosities range from about 5000 to about 9000 centipoise at 27 C. (as measured by a Wells-Brookfield model RVTDCP viscometer using a CP-41 cone and plate at 2/s at 3 minutes).
Comparative Examples 1 to 7 and Examples 8 to 12 NEODOL 23, a C12/C13 primary alcohol composition, is commercially available from The Shell Chemical Company. Hexadecanol and 2-undecanol are available from Aldrich and 4-tridecanol is available from Chemical Samples Co, Columbus, Ohio, USA. Comparative Examples 1 to 7 and Examples 8 to 12 of the present invention are carried out according to the following process unless otherwise indicated in Table 1. Under a nitrogen atmosphere the alcohol, solvent-1 and the base were reacted for 1 h under the conditions detailed in Table 1, in order to form a sodium alkoxylate mixture. Ethylene sulfate (available from Eastar Chemical Corporation, Sacramento, Ca, USA) dissolved in solvent-2 was added to the stirred sodium alkoxylate mixture at such a rate that the designated temperature could be maintained. The reaction mixture was then stirred at the indicated temperature overnight. At the times indicated in Table 1, small samples were taken. These samples were hydrolysed by treatment with 6N H2SO4 at 90C for less than 1h and subsequently analysed by gas chromatography (GC). GC was carried out on a Hewlett-Packard HP6890 apparatus with the following column: Varian-Chrompack capillary column CP-SM 5CB (low-bleed), length 50 m, internal diameter 0.25 mm, film thickness 0.4 mum and with the following temperature program: 125 C (5 min); 125 - 325 C (10 C/min); 325 C (5 min). Flame ionization detection and an internal normalization method of quantification were employed.; Table 1: Preparation of Alcohol Ethoxysulfates Example Alcohol (mmol) Base (eq) Solvent-1Ethylene sulfatea (eq) Solvent-2 Temp (C) Time (h)Conversionb (%) Remarks 1* Neodol 23 KOH (0.05) toluene 1.0 toluene 90 <½12c prepared according to WO 96/035663 (50)Na2CO3 (1.0) water toluene 40 ½ 2* hexadecanol (20) NaOH (1.0) toluene 1.0 toluene 20 24 10 water removal with Dean-Stark setup at 130C 3* Neodol 23 Na (1.0) p-dioxane 1.0 p-dioxane 20 ½ 59 deprotonation at (50) 20 24 63 120C for 20h 4* 4-tridecanol (50) Na (1.15) p-dioxane 1.0 p-dioxane 20 2 54 deprotonation at 120C for 18h 5* Neodol 23 (50)NaHCO3 (1.0) water 1.0 p-dioxane 90 1622d 6* 4-tridecanol NaOH (1.5) p-dioxane 1.3CH2Cl2 <25 ½ 0 (50) 24 0 7* 4-tridecanol (50) NaOH (1.5) p-dioxane 1.3 p-dioxane <25 ½ 0 8 Neodol 23 NaOH (5.0) DMSO 1.0CH2Cl2 20-40 ½ 65 (50) 40 20 66 +0.5 40 6 76 +0.5 <25 ½ 84 9 Neodol 23 NaOH (1.5) sulfolane 1.0CH2Cl2 <25 ½ 49 minimum amount (50) 20 49CH2Cl2 to lower the viscosity. 10 2-undecanol (50) NaOH (1.5) DMSO 1.3CH2Cl2 <25 ½ 48 11 2-undecanol (50) NaOH (5.0) DMSO 1.3CH2Cl2 <25 ½ 57 12 Neodol 23 (50) NaOH (5.0) DMSO 1.3CH2Cl2 <0 0-20 24 69 <0C during addition; then slowly heated to 20C 13 Neodol 67 (300) NaOH (5.0) DMSO 1.3CH2Cl2 <25 1 -69 * Comparative Example. a. Ethylene sulfate is available from Eastar Chemical Corporation, Sacramento, Ca, USA and has been used without purification. b. Measured by GC after hydrolysis in 6N sulphuric acid at 90C for <1h (wt% of 1EO-adduct on alcohol intake). c. Trace (<1%) of 2EO derivative also present. d. 2EO and 3EO derivatives also observed in GC after hydrolysis.
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).
Various phosphocholine derivatives were synthesized using a three-step process as shown in FIGS. 1-2. Specifically, 0.484 grams of hexadecanol (n=15) (from Aldrich Chemical Company) was mixed with 20 milliliters of toluene and 100 milliliters of phosphoryl chloride (?POCl3?). The mixture was heated in an oil bath at 87 to 90 C. for 5 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuum. 50 milliliters of methylene chloride and 1.38 grams of choline tosylate were then stirred into the mixture at room temperature for 40 to 50 hours. This reaction mixture was concentrated by a rotavaporator and the resulting residue was mixed with 1.5 milliliters of water. The residue was stirred at room temperature for 5 hours and concentrated with a nitrogen stream to give crude hexadecyl phosphocholine. Tetradecyl phosphocholine (C14 chain) and docosanoyl phosphocholine (C22 chain) were also synthesized using the technique described above, except that tetradecanol (n=13) and docosanoyl alcohol (n=21) were used to as starting materials instead of hexadecanol. Further, as shown in FIG. 2, the procedure set forth above was also used to synthesize hexadecyl thiophosphocholine, except that thiophosphoryl chloride was used instead of phosphoryl chloride. The expected molecular ion and the corresponding mass spectral results for each synthesized phosphocholine or thiophosphocholine derivatives were determined using mass spectral analysis. The results are shown below in Table 1.
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;Inert atmosphere;
Preparation of 4-{5-[Bis-(chloroethyl)-amino]-l-methyl-lH-benzimidazol-2-yl}butyric acid pentadecyl ester (<strong>[3543-75-7]bendamustine</strong> Ci ester): A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10.0 g (25.34 mmol) of <strong>[3543-75-7]<strong>[3543-75-7]bendamustine</strong> hydrochloride</strong>, 5.85 g (25.6 mmol, 1.01 eq) of pentadecanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction was stirred at room temperature overnight at which time an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was washed with saturated aqueous sodium bicarbonate solution (2 X 100 mL), DI water (1 X 100 mL) and brine (1 X 100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to an off-white solid. This solid was triturated with 25 mL of MDC and the solid impurities were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was concentrated to dryness in vacuo to yield 10.8 g (19.0 mmol, 75%) of the product as an off-white solid with an HPLC purity of 94.6A%. NMR (400 MHz, CDC13) delta 7.17 (d, J= 8.76 Hz, 1H), 7.08 (d, J= 2.32 Hz, 1H), 6.78 (dd, J= 2.4, 8.76 Hz, 1H), 4.05 (t, J= 6.8 Hz, 2 H), 3.72 (m, 4H), 3.69 (s, 3H), 3.63 (m, 4H), 2.91 (t, J= 7.4 Hz, 2H), 2.49 (t, J= 7.08 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 24H), 0.88 (t, J= 6.68 Hz, 3H).
at 130 - 140℃; under 37.5038 - 75.0075 Torr; for 8.0h;Green chemistry;
General procedure: To a suspension of dried Glycine Betaine (8.3g, 71mmol, 1.0 equiv.) in methanesulfonic acid (1.5 equiv.), an excess of n-alcohol (about 2 equiv.) was added. The reaction mixture was gradually heated to 130-140C under reduced pressure (50-100mbars) to remove the water formed during the reaction. After 1h, the reaction mixture became homogeneous and after 7h the brown mixture was cooled down to room temperature and at atmospheric pressure. The crude material was washed with Et2O (3×200mL) to remove the excess of fatty alcohol and then purified by recrystallisation from EtOAc/EtOH (1/1). For (GBOC16-CH3SO3) the purification was done by column chromatography over silica gel using EtOAc/iPrOH/H2O (62/30/8) as eluent. 2.3.2.3 Hexadecylbetainium methanesulfonate (GBOC16-CH3SO3) Yield (18.9 g, 43.3 mmol, 61%). Melting point 105 C. 1H NMR: deltaH (250 MHz; DMSO-d6): 0.95 (3H, t, J = 7.5 Hz, CH3), 1.33 (26H, m), 1.70 (2H, q, J = 7.5 Hz, CH2CH2O), 2.39 (3H, s, CH3-S), 3.31 (9H, s, (CH3)3N), 4.27 (2H, t, J = 7.5Hz, CH2O), 4.54 (2H, s, CH2COO). 13C NMR: deltaC (62.5 MHz; DMSO-d6): 14.2 (CH3), 28.4, 29.4, 29.6, 29.7, 29.8, 29.8, 32.0 (CH2), 39.6 (CH3S), 54.0 (CH3)3, 63.1 (CH2O), 66.8 (CH2CO), 165.2 (C=O). IR: nu(cm- 1) 1751 (C=O). Analysis: Calculated for C22H47NO5S: C 60.37, H 10.82, N 3.20, S 7.33%. Found: C 60.17, H 10.72, N 3.23, S 7.36%.
To a solution of (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1- [(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid (<strong>[81846-19-7]treprostinil</strong>) (78.1 mg, 200 mumoles) dissolved in 1,4-dioxane (2.0 mL) was added Amberlyst 15 resin (2.0 g) and alcohol R2-OH (2.0 mmoles, 10 equivalents). The reaction mixture was heated to 40 C and allowed to shake at approximately 100 rpm for 18-196 hours. Solvent was removed and the resin was washed with acetonitrile (MeCN) (3 x 3 mL). The 1,4-dioxane and MeCN extracts were combined and dried using a gentle stream of warmed N2 gas and gentle heat to yield a thick waxy solid. The crude material was dissolved in 20% nPrOH/Hexanes and submitted to preparatory HPLC purification. Solvent was removed from the purified material using a gentle stream of warmed N2 gas and gentle heat to yield an off-white waxy solid. The pure material was suspended in ethyl lactate for storage and was submitted to analytical HPLC for concentration determination. [00224] By way of example, the following compounds of Formula (A) were synthesized by the method of scheme 2.
With Amberlyst-15; In 1,4-dioxane; for 18h;
General procedure: A general diagram for synthesis of the alkyl ester of <strong>[81846-19-7]treprostinil</strong> is shown in Scheme 1, below as well as Figure 1. The alcohol can be modified based on the desired alkyl ester chain length (e.g., C5-C18 alkyl esters of even or odd chain length, straight chain or branched). Other reaction conditions used to synthesize <strong>[81846-19-7]treprostinil</strong> ester prodrugs are provided in Table 6, below
With Amberlyst 15 resin; In 1,4-dioxane; at 40℃;
General procedure: To a solution of (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3- hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid (<strong>[81846-19-7]treprostinil</strong>) (78.1 mg, 200 mumoles) dissolved in 1,4-dioxane (2.0 mL) was added Amberlyst 15 resin (2.0 g) and alcohol R2-OH (2.0 mmoles, 10 equivalents). The reaction mixture was heated to 40 C and allowed to shake at approximately 100 rpm for 18-196 hours. Solvent was removed and the resin was washed with acetonitrile (MeCN) (3 x 3 mL). The 1,4-dioxane and MeCN extracts were combined and dried using a gentle stream of warmed N2 gas and gentle heat to yield a thick waxy solid. The crude material was dissolved in 20% nPrOH/Hexanes and submitted to preparatory HPLC purification. Solvent was removed from the purified material using a gentle stream of warmed N2 gas and gentle heat to yield an off-white waxy solid. The pure material was suspended in ethyl lactate for storage and was submitted to analytical HPLC for concentration determination.
General procedure: In a round-bottom flask, acrylic acid and fatty alcohol were taken in a 1:2 molar ratio followed by the addition of 0.5 % w/v of NaHSO4 (with respect to acrylic acid). The reaction mixture was stirred at 110 C and the progress of the reaction was monitored by TLC as well as GC. Both fatty acrylate and 3-(alkyloxy)-3-oxopropyl acrylate were found to be formed nearly in equal proportion within 2 h, as indicated by GC analysis. After 2 h, the reaction mixture was solubilized in hexane and washed with water to remove unreacted acrylic acid and NaHSO4, dried overanhydrous Na2SO4 and concentrated using rotaryevaporator to get the crude product. Finally, the reaction mixture was purified by column chromatography using hexane and ethyl acetate as eluent. The fatty acrylate was eluted with 0.3 % ethyl acetate in hexane and 3-(alkyloxy)-3-oxopropyl acrylate was eluted with 0.5 % ethyl acetate in hexane.
General procedure: To a solution of <strong>[3482-49-3]fusidic acid</strong> (1.0 equiv.) in dichloromethane (6 mL) was added DMAP (2.50 equiv.) and EDCI (2.50 equiv.). The reaction mixture was stirred at 25C for 10 min followed by addition of corresponding alcohol (1.2 equiv.). The resulting reaction mixture was stirred for 12h at 25C. The reaction mixture was washed with saturated aqueous ammonium chloride (2 x 15 mL) and distilled water (3 x 15 mL), organic layer was dried over MgSO4 and concentrated under reduced pressure to give a crude product. The crude product was subjected to column chromatography on silica gel using ethyl acetate/hexane as eluent to furnish the target compounds.
With sodium bromate; sulfuric acid; sodium bromide; In water; at 20℃; for 24.0h;
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 98% 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 98% yield (0.953 g) as colorless liquid. The product was confirmed by GC-MS as well as by NMR.
With Lipozyme from Rhizomucor miehei RM1M; In di-isopropyl ether; at 55℃;Green chemistry; Enzymatic reaction;
General procedure: LIP (10mg) was added to a solution of hyodeoxycholic acid (20mg) and the corresponding alcohol (1eq.) in diisopropyl ether (DIPE) (5mL). The suspension was shaken (200rpm) at 55C and the reaction monitored by TLC. Once the reaction was finished, the enzyme was filtered off and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel employing mixtures of hexane:ethyl acetate as eluent (1:0-1:1). Reuse experiments: the filtered and washed enzyme was used in the next enzymatic esterification under the same reaction conditions. LIP retained 80% activity after three reaction cycles.
<strong>[95809-78-2]6,8-bis(benzylthio)octanoic acid</strong> (5.0 g) was dissolved in anhydrous THF (100 mL). The stirring solution was cooled to 0 C and triethylamine (3.7 mL) added. The cold reaction was stirred 10 min and ethyl chloroformate (1.4 mL) added slowly. The reaction was stirred at 0 C for 20 min then cetyl alcohol (3.3 g) was added. After stirring for 20 min the cooling bath was removed and the reaction stirred to room temperature overnight. A solution of 5% citric acid (75 mL) was added and the mixture stirred for 10 min then the two phases separated. The organic layer was washed with saturated sodium bicarbonate, brine, water and dried over sodium sulfate. After filtration of the solids, the volatiles removed under reduced pressure at less than 20 C. The waxy solid was stored at 5 C.
equipped with a thermometer, a water separator,156 g (0.91 mol) of <strong>[2840-28-0]3-amino-4-chlorobenzoic acid</strong>, 264 g (1.09 mol) of n-hexadecanol, 45 g of toluene, and 182 g of xylene were respectively added to a three-necked flask of a stir bar, and the mixture was heated to 50 C with stirring, and kept at a constant temperature for 1 h. After n-hexadecanol was completely dissolved, 18.8 g (0.109 mol) of p-toluenesulfonic acid was added.Heating was continued at a reflux temperature of 152 to 164 C for 10 h to stop the reaction.Add 1500 mL of methanol, cool to 20 C, crystallization time 5 h, filter,After the filter cake was dried, 292 g of a crude product was obtained, and 1500 mL of the first filtrate was collected.Add 1500 mL of methanol to the crude product, heat to 70 C to be completely dissolved, and cool to 10 C.Recrystallization time 8h, filtration, drying the filter cake to obtain 284g finished productHexadecyl 3-amino-4-chlorobenzoate, yield 78.81%,A second filtrate of 1500 mL was collected. HPLC test analysisThe purity of hexadecyl 3-amino-4-chlorobenzoate was 98.50%.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃;
General procedure: The synthesis of the AKGs was performed following the literature with some modifications (Baumann and Mangold 1964; Hanus et al. 2001; Appendino et al. 2003; Parkkari et al. 2006). LiAlH4 (550 mg, 14.5 mmol) was added slowly to a solution of the corresponding methyl ester (3.4 mmol) in anhydrous tetrahydrofuran (15 mL) at 0C and stirred for 1 h and was then left at 20C for 20 h. The reaction mixture was washed with NaOH (10%) followed by HCl (10%) and extracted with diethyl ether (3 × 20 mL); the extract was neutralized with saturated NaHCO3, dried under reduced pressure and purified by CC. The alcohol obtained was subsequently mesylated in absolute pyridine (4.5 mL, 55.6 mmol) at 0C by the addition of MsCl (880 mg, 7.65 mmol) and the solution was maintained for 24 h at 20C. After quenching the reaction with 5 mL of degasified water, the solution was extracted with diethyl ether (4 × 20 mL). The organic phase was washed with H2SO4 (2 N), neutralized, concentrated in vacuo, and the crude mesylate was purified by CC. KOH (127 mg, 2.26 mmol) was added to the chiral precursor (R)-solketal (283 mg, 2.14 mmol) in anhydrous toluene (2 mL). The reaction stirred at 50C for 1 h before the addition of metallic Na (3 mg, 0.15 mmol) followed by the mesylate dissolved in toluene (15 mL), and the resulting mixture was kept at 50C for 72 h. The reaction was quenched with HCl (10%) and extracted with ethyl ether (4 × 20 mL). The organic phase was neutralized, concentrated and purified by CC to give 1-O-alkyl-2,3-O-isopropylidene-sn-glycerol. This intermediate was deprotected in 5 mL of HCl:MeOH (1:10 v/v) and refluxed overnight. After the addition of H2O (10 mL) and extraction with diethyl ether (4 × 20 mL), the organic phase was neutralized, evaporatedto dryness in vacuo, and the residue was purified by CC to afford pure AKGs. Each step in the synthesis was monitored by TLC, and all CC steps were eluted with hexane-toluene-ethyl acetate (10:0:0-0:10:0-0:0:10) mixtures. The structures of the synthesised compounds were confirmed by 1H, 13C APT NMR with COSY, HMQC, HMBC and ESI-MS or HRESI-MS spectra along with the specific optical rotation.