* 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.
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[ 112-05-0 ]
[ 2104-19-0 ]
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[7] Patent: WO2011/80297, 2011, A1, . Location in patent: Page/Page column 9-10
[8] Patent: US2012/245375, 2012, A1, . Location in patent: Page/Page column 4
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In a three-neck 500 mL flask, 30.0 g (0.196 mol) of vanillin was added.31.0 g (0.196 mol) of n-decanoic acid and 300 mL of toluene were added.Boric acid 0.6g (9.8mmol), a three-neck flask fitted with a thermometer,A mouth water separator + reflux condenser (the water separator is loaded into the reaction flask,Then install the reflux condenser above the water separator.)Another mouth is closed, stirring is started, and the temperature is raised to 130°C for 8 hours.After the reaction is completed, it is cooled to room temperature.Add 50mL of water twice to wash (extract boric acid),After drying over anhydrous sodium sulfate,Recovery of toluene under reduced pressure at 60 °C using a rotary evaporatorTo the distillation of toluene is 2/3 of the original volume, stop decompression recovery,The remaining liquid is transferred to the cryogenic reactor,Stir and crystallize at -20°C for 3h, filter,The resulting crystals are washed with toluene.Drained to give 50.3 g of a white powdery solid with a yield of 87.4percent.HPLC purity 99.1percent.White powder solids analysis:
74%
With Candida antarctica lipase B In toluene at 80℃; for 36 h; Inert atmosphere; Molecular sieve; Enzymatic reaction
A microwave-vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), ammonium formiate (37.8 mg, 0.6 mmol, 3.0 equiv.) and Pd°-catalyst(Pd°-AmP-MFC, 13.4 mg, 0.01 mmol, 8 wtpercent, 5 molpercent) or(Pd°-CPG, 569A, 74.0 mg, 0.013 mmol, 6.6 molpercent) in toluene (1 mL) under ISfc conditions was stirred at 80°C for the time shown in Table 3. Afterwards, molecular sieves 4A, acid 4 (0.2 mmol, 1.0 equiv.) and lipase (120 mg/mmol) were added to reaction mixture and stirred at 80°C for 36h. The crude reaction mixture was filtrated through Celite using CHCb(10 mL) as eluent and evaporated. The crude material was purified by silica gel flash column chromatography to afford the corresponding amide 3 as indicated in Table 3. The lipase is preferably Novozyme-435 immobilized on a macroporous anionic resin.
52%
With lipase In tert-Amyl alcohol at 45℃; for 48 h; Molecular sieve; Enzymatic reaction
The dried crude reaction mixture from the previous step (containing vanillylamine 94 mg, 0.62 mmol, 1.00 equiv.) was dissolved in 2-methyl-2-butanol (31 mL, 20 mM). To the reaction was added Ms 4A (2 g), compound 5b (98.7 mg, 0.62 mmol, 1.00 equiv.) and lipase (1.9 g, 20 mg/niL). The reaction was stirred at 45°C for 48 h. Afterwards the reaction was cooled to room temperature and filtered. The solvent was removed under reduced pressure and the crude material was purified by chromatography to afford nonivamide (7b) (isolated yield 52 percent) as light yellow oil.
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Yield
Reaction Conditions
Operation in experiment
81.1%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 0 - 20℃;
Into a reactor equipped with a heating, stirring, and a thermometer, 112 g of vanillin amine hydrochloride obtained above was added to 670 ml of a DMF solvent, and the mixture was stirred at room temperature until the solid was completely dissolved and 95.2 g Nonanoic acid was added thereto.The was cooled to 0°C with an ice bath, 134.4g of triethylamine was added, the temperature was stabilized at 0-5°C, and 235.2g of a condensing agent HBTU was added under stirring. The reaction was naturally warmed to room temperature and stirred overnight. After the reaction was completely detected by TLC, Add 1100 ml of ethyl acetate and 330 ml of water to the reaction mixture. Stir well and place in liquid in a separatory funnel. Discard the aqueous layer and obtain ethyl acetate layers of 5 wtpercent sodium bicarbonate solution, 2 wtpercent hydrochloric acid, respectively. The saturated brine was washed three times each, 1200 ml/time, and then 100 g of anhydrous sodium sulfate was added to the ethyl acetate layer for drying for 3 hours. The sodium sulfate was removed by filtration, and the filtrate was placed in a reactor and heated to 45° C. with stirring and reduced. About 820 ml of ethyl acetate was distilled off and cooled to room temperature. 540 ml of petroleum ether was added to crystallize for 3 hours and filtered. The solid was dried at 40-45° C. for 10 hours to obtain 156.4 g of Nonivamide as the target product. The total yield was 81.1percent. The obtained capsaicin was analyzed by HPLC and its purity was 98.8percent.
With polymer supported sulfonated magnetic resin In toluene at 20 - 70℃; for 0.75h;
General experimental procedure
General procedure: A mixture of 50 mg polymer supported sulfonated magnetic resins (0.1 mmol) and alkyl alkylphosphonic acid/carboxylic acid (1 mmol) and dry toluene (0.5 ml) was stirred at room temperature for 15 min. After that excess of alcohol (4 mmol) was added to the reaction mixture and stirred at 70 °C for further 30 min. Progress of the reaction was monitored by TLC and 31P NMR. After completion, the reaction mixture was cooled to room temperature and placed nearby a strong external magnet and supernatant layer was separated from the reaction mixture. Finally, excess of solvent was removed by distillation to get the colourless liquid. 1H and 31P NMR spectra at 400 MHz were recorded in CDCl3. Electron ionization (EI+) mass spectra were recorded on Agilent GC-MS system
With toluene-4-sulfonic acid; benzene
With sulfuric acid; benzene unter Entfernen des entstehenden Wassers;
With thionyl chloride;N,N-dimethyl-formamide; at 50℃; for 2.25h;
Example 9 Purification of Pelargonoyl chloride (Nonanoyl Chloride) 0.4 g (0.005 mol) of N,N-dimethylformamide were added to 158 g (1.0 mol) of pelargonic acid, and the mixture was heated to 50 C. At 50 C., a total of 125 g (1.05 mol) of thionyl chloride were added dropwise over the course of 45 minutes.. After a post reaction time of 30 minutes at 50 C., nitrogen was passed through the mixture at 50 C. for 1 hour, and sulfur dioxide, hydrogen chloride gas and unreacted thionyl chloride were stripped out.. The pale yellow product had a color number of 113 APHA and, according to GC analysis, comprised 99.5 area % of pelargonoyl chloride. 20 ml of the product were vigorously stirred with 5 ml of DMF hydrochloride from synthesis 1 in a stirred apparatus, and then the phases were separated.. The pelargonoyl chloride phase was stripped until HCl-free using nitrogen.. The color number was then only 37 APHA.
With phosgene;N,N-dimethyl-formamide; at 20 - 30℃;
100.5 g (1.38 mol) of N,N,-dimethylformamide were added to 2.75 mol of pelargonic acid in a stirred apparatus.. The reaction solution was brought to a temperature of from 20 to 30 C. with stirring, and a total of 2.78 mol of gaseous phosgene were introduced under atmospheric pressure.. After the addition of phosgene was complete, the two phases were separated from one another.. The catalyst phase comprised a molar proportion of the catalyst adduct, based on the molar amount of N,N-dimethylformamide plus catalyst adduct, of <0.05.. The carbonyl chloride phase comprised 97.1 area % of pelargonoyl. chloride and 1.9 area % of pelargonic anhydride.. The color number was 16 APHA. As a result of a very low, virtually stoichiometric molar ratio between the phosgene introduced and the pelargonic acid used, only an unsatisfactorily low content of pelargonoyl chloride was achieved in the crude product, with too high a content of pelargonic anhydride.. However, the carbonyl-chloride-containing phase exhibits a very low color number.
With hydrogenchloride; phosgene;N,N-dimethyl-formamide; at 20 - 30℃;
100.5 g (1.38 mol) of N,N-dimethylformamide were added to 2.75 mol of pelargonic acid in a stirred apparatus.. The reaction solution was brought to a temperature of from 20 to 30 C. with stirring, and a total of 2.78 mol of gaseous phosgene and simultaneously 1.92 mol of gaseous hydrogen chloride were introduced under atmospheric pressure.. When the addition of phosgene and hydrogen chloride was complete, the two phases were separated from one another.. The catalyst phase comprised a molar proportion of the catalyst adduct, based on the molar amount of N,N-dimethylformamide plus catalyst adduct, of 1%.. The carbonyl chloride phase comprised 98.9% by weight of pelargonoyl chloride and 0.04% by weight of pelargonic anhydride.. The color number was 18 APHA. Only as a result of the simultaneous introduction of hydrogen chloride according to the invention was it possible to obtain a high conversion to pelargonoyl chloride having a very low color number.
With oxalyl dichloride; In dichloromethane; at 0 - 20℃; for 2h;
A solution of 2-(oxazol-5-yl)pyridine (117 mg, 0.80 mmol) in anhydrous THF (5 mL) cooled to -75 C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.88 mmol, 0.35 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.60 mmol, 3.2 mL) was added at -75 C., and stirred for 45 min at 0 C. Cul (1.0 equiv, 0.80 mmol, 152 mg) was added, and the solution was stirred for 10 min at 0 C. A separate flask was charged with nonanoic acid (2 equiv, 1.60 mmol, 253 mg, 0.28 mL) in anhydrous CH2Cl2 (4.2 mL), and to this solution cooled to 0 C. under N2 was added oxalyl chloride (5 equiv, 8.0 mmol, 1.02 g, 0.70 mL). After stirring at rt for 2 h, the solution was concentrated under reduced pressure and dissolved in anhydrous THF (1.5 mL). The solution of nonanoyl chloride was added and the solution was stirred for 1 h at 0 C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)nonan-1-one (188) (94 mg, 0.33 mmol, 41% yield) as a light brown powder: mp 56-57 C.; 1H NMR (CDCl3, 250 MHz) d 8.61 (br d, J=4.4 Hz, 1H), 7.84-7.71 (m, 3H), 7.29-7.22 (m, 1H), 3.05 (t, J=7.3 Hz, 2H), 1.79-1.66 (m, 2H), 1.42-1.16 (m, 10H), 0.88-0.77 (m, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.4, 157.3, 153.1, 150.0, 146.2, 137.0, 126.8, 124.0, 120.3, 39.0, 31.7, 29.2, 29.0, 24.0, 23.9, 22.5, 14.0; IR (KBr) umax 2922, 2856, 1705, 1697, 1600, 1420, 1381 cm-1; MALDI-FTMS (DHB) m/z 287.1744 (C17H22N2O2+H+ requires 287.1754).
With thionyl chloride; at 80℃; for 16h;
General procedure: In a 250 ml round bottom flask dried previously, wasadded 1 ml of nonanoic acid (11 mmol) and 0.6 ml of thionylchloride (8.30 mmol), the reaction mixturewas stirred and refluxedfor 16 h at 80 C. Later, the reaction mixture was cooled at roomtemperature and under vigorous stirring was rapidly added 6(0.89 mmol, 200 mg) to reaction medium, followed of 2 ml ofpyridine. The mixture reaction was stirred at room temperature for2 h and then partitioned between an aqueous acid solution anddichloromethane; the organic layerwas extracted and washed witha saturated aqueous solution of sodium chloride. After theconcentrated organic layer was hydrolyzed in presence 2 ml of asolution sodium hydroxide 0.1 M in 10 ml of methanol and wasrefluxed for 3 h under stirring. The hydrolysis mixturewas acidifieduntil pH 4 with hydrochloric acid 37%, a white precipitate wasformed and then filtered followed of the purification by columnchromatography using 20% ethyl acetate/hexane, and finally theproduct obtained was crystallized in 1:4 water/methanol to give 8as white crystals.
With trichloroacetamide; triphenylphosphine; In dichloromethane; for 1h;Reflux;
General procedure: To a 250-mL round-bottomed flask was added the corresponding carboxylic acid (25 mmol), trichloroacetamide (8.12 g, 50 mmol), triphenylphosphine (13.11 g,50 mmol), and dichloromethane (100 mL) to give a colorless solution. The mixture was stirred and heated at reflux for 1 h. Then, solketal (3.11 mL, 25 mmol) and pyridine (6.04 mL, 75 mmol) were added to the resulting acid chloride solution and the reaction mixture was heated at reflux until completion as indicated by TLC (approximately 4 h). After completion, the solution was extracted with 10% HCl and sat. aq. NaHCO3, dried over Na2SO4 and evaporated. The crude product was purified with a silica gel column eluting with 5% EtOAc/hexane (Scheme 2).
With oxalyl dichloride; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
In a 2 liter, two neck round bottom flask, 20 g octanoic acid dissolved in DCM (200 ml) was taken and then added 1.5 eq. oxalyl chloride slowly at 0 C., stirring under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours.
With thionyl chloride;Reflux;
General procedure: 45 g (50 mL, 0.346 mol) of enanthic acid was slowly added dropwise to 124 g (75 mL,1.042 mol) of thionyl chloride upon reflux. The obtained mixture was heated upon reflux for 30 min, and the excess thionyl chloride was evaporated in vacuum. About 50 g of enanthoyl chloride was obtained as a yellow oil. 25 g (0.102 mol) of 5,7-dimethyl-1,3-bis(hydroxymethyl)adamantane, 70 mL of triethylamine, 50 g (0.337 mol) of enanthoyl chloride, and 200 mL of toluene are placed into a three-neck flask equipped with a mechanical stirrer and a reflux condenser. The obtained mixture is heated upon reflux for 3 h. The formed precipitate of triethylamine hydrochloride is filtered off, and the filtrate is evaporated in vacuum on a rotary evaporator. The residue is purified via vacuum distillation collecting a fraction with bp 200-202C (0.036 Torr). The weight 37 g, yield 74%,
EXAMPLE 1; Step a); The following substances were fed continuously to a CSTR with a working capacity of 80 1, equipped with stirrer and with an adequate temperature regulation system:methyl oleate (technical purity approximately 85%; flow rate 10 kg/h);an aqueous solution of hydrogen peroxide at 60%> (flow rate 2.3 kg/h);- tungstic acid (H2W04) (flow rate 48 g/h).The reaction was conducted at a constant temperature of 62C under vacuum (absolute pressure of 0.10-0.20* 105 Pa) to evaporate the water fed together with the hydrogen peroxide; the evaporated gas was collected and condensed (approximately 1 kg/h of water).FIG. 3 shows the hydrogen peroxide over-all concentration during step a).As can be seen in Fig. 3, the over-all hydrogen peroxide concentration in the reactor was constant at about 1.5 g/kg.The intermediate product containing vicinal diols was continuously discharged from the reactor and fed to step b) by means of a gear pump, adjusted to maintain a constant level in the reactor, with a flow rate of approximately 11.4 kg.; Step b; Step b) was performed in a jet loop reactor with a working capacity of 80 1 equipped with a 3 m3/h recirculation pump and heat exchanger. The intermediate product of step a) was continuously fed with a flow rate of 11.4 kg/h together with:cobalt acetate (Co(CH3COOH)2»4H20, dissolved at 1.5% in an aqueous current(approximately 2 kg/h);- pressurized air (20* 105 Pa; flow rate 12 to 15 kg/h).The air flow rate was adjusted to maintain a constant 02 content (approximately 10%) at the reactor outlet.The reaction was conducted at 60C, keeping constant the reaction volume to 50 1. The reaction time was about 3.5h.The reaction mixture of step b) was continuously discharged from the jet loop reactor and fed to a decanter to separate the oily phase from the aqueous phase. Approximately 13 kg/h of oily product was obtained.; Step (c); The separated oily phase was dried and degassed, and then transferred to a distillation column which allowed fractioning of the monocarboxylic acids, to separate the pelargonic acid from the lighter monocarboxylic acids. The main component of the lighter monocarboxylic acids fraction (byproducts of the oxidative cleavage reaction) was octanoic acid.Approximately 3.8 kg/h of vapor phase containing monocarboxylic acids (raw pelargonic acid), of which 3.5 kg/h are pelargonic acid with a titer of over 99%, was obtained. The 3.8 kg/h current of raw pelargonic acid contained approximately 3.3% of octanoic acid.An organic current of approximately 9 kg/h, containing as major component mono-methyl azelate, together with methyl palmitate, methyl stearate and esters of methyl dihydroxy stearate, was extracted from the bottom of the distillation column.Said organic current was then continuously fed to an emulsifier together with 18 kg/h of water. The emulsion was hydro lyzed by feeding it to three consecutive columns filled with acid ion exchange resin and heated at the temperature of 100C. The total reaction time was 6 h.Each column was provided with a fractionating column on the top, to separate 1.1 kg/h of methanol from water. Approximately 8.5 kg/h of carboxylic acids were obtained from the bottom of the column, of which about 4.3 kg was azelaic acid.
Example 1Comparative ExampleOzonolysis and Oxidation without Addition of Acid20 g of a 0.182 molal solution of methyl oleate (95% pure) in a solvent mixture of propionic acid and water (15 equivalents based on moles of double bond) were initially charged in a two-neck flask with gas inlet tube and reflux condenser. The feed gas, consisting of 5% by volume of oxygen in carbon dioxide was passed through an ozone generator at a flow rate of 40 ml/min. The ozone generator was set to maximum power. The ozone-containing gas mixture was passed into the reaction mixture with stirring. The offgas stream was passed by means of gas wash bottles into a 5% aqueous potassium iodide solution. After 60 minutes, the substrate was converted, and the gas introduction was then stopped. According to GC analysis, the reaction mixture had a content of 39.5 wt % of 9-nonanal and 38.2 wt % of methyl 9-oxononanoate.After adding hydrogen peroxide (0.454 g of a 30% aqueous solution), the reaction mixture was then heated to 100 C. in an oil bath. After 120 minutes, nonanal and methyl 9-oxononanoate were converted completely to the respective carboxyl compounds. GC analysis: 41.05% pelargonic acid, 39.65% monomethyl azelate (FID signal, figure in area percent, uncorrected).
With [ReOCl2(1,2-bis(diphenylphosphino)ethane)]; hydrogen; potassium tetraphenylborate In toluene at 150℃; for 30h; Autoclave; Inert atmosphere;
8
General procedure: By the following method, it went 3-reduction of phenylpropionic acid (hydrogenation).Put a stir bar in a dry glass tube (25mL), further, 3-phenylpropionic acid (75.09mg, 0.5mmol), the rhenium complex 4 (7.07mg, 0.010mmol), potassium tetraphenylborate (17.92mg , accommodates 0.05 mmol), the tubes containing this mixture, was inserted into the autoclave. Then, after replacing the inside of the autoclave in an argon gas atmosphere was added while continuing flow of argon gas dehydration toluene (4.0mL). This autoclave through a stainless steel tube by introducing hydrogen gas from a hydrogen gas cylinder connected, the inside of the autoclave was replaced with hydrogen gas, then disconnect the hydrogen gas pressure from the leak valve. This operation - was repeated (substituted de substitution) five times. Finally, the hydrogen gas pressure in the autoclave was set to 4 MPa, using a constant temperature bath, and allowed to react for 12 hours at 180 ° C. After completion of the reaction, the autoclave was cooled by immersion in an ice bath, almost to room temperature. Then, carefully release the hydrogen gas that is inside in the draft. After removing the solvent, the reaction product was analyzed by 1H NMR using mesitylene (60.1 mg, 0.5 mmol) as an internal standard substance. As a result, 3-phenylpropyl alcohol, and 3-phenylpropionic acid 3-phenylpropyl The yield was 98% and 1%, respectively. In the above Examples 6-1,Substrate (carboxylic acid compounds), and hydrogenation conditions (hydrogen pressure),Except that to adopt the conditions described in Table 7-9,It has been reduced (hydrogenated) in the same manner as in Example 6-1.However,The entry 19-26 in Table 9,Using tetrahydrofuran (THF) as a solvent.The results are shown in Tables 7 to 9.
96.9%
With hydrogen In hexane at 250℃; for 3h;
93%
With sodium tetrahydridoborate; titanium(IV) tetrachloride In 1,2-dimethoxyethane for 14h; Ambient temperature;
93%
With sodium tetrahydridoborate; trifluoroacetic acid In tetrahydrofuran at 25℃; for 4h;
93%
With sodium tetrahydridoborate; trifluoroacetic acid In tetrahydrofuran at 25℃; for 4h; multistep reaction: with catechol; other aliphatic and aromatic acids;
90%
With sodium tetrahydridoborate; Sodium sulfate [anhydrous]; dihydroxy(3,4,5-trifluorophenyl)borane In tetrahydrofuran at 20℃; for 10h;
96 % Chromat.
With samarium diiodide; Octanal; samarium(III) trifluoromethanesulfonate In tetrahydrofuran; methanol; potassium hydroxide at 20℃; for 0.075h;
66 %Spectr.
Stage #1: nonanoic acid With phenylsilane; C32H25MnN4O3P(1+)*Br(1-) In tetrahydrofuran at 80℃; for 2h;
Stage #2: With lithium hydroxide monohydrate In tetrahydrofuran
89 %Chromat.
With hydrogen In lithium hydroxide monohydrate; isopropanol; Bicyclo[4.4.0]decane at 170℃; for 5h; Autoclave;
General procedure: At ozone generator output 40 mmol O3/h through a solution of 1.41 g (5.0 mmol) of oleic acid 1 in 25 mL of anhydrous alcohol or 20 mL of anhydrous THF or 25 mL of a mixture AcOH-CH2Cl2, 1 : 5, at 0 C was bubbled ozone-oxygen mixture till 5.5 mmol of ozone was consumed. The reaction mixture was flushed with argon and then it was treated by two procedures. a. At 0 1.20 g (17.3 mmol) of NH2OH·HCl was added, the mixture was stirred at room temperature till disappearance of peroxides (iodine-starch test). The solvent was distilled off, the residue was dissolved in CHCl3 (50 mL), the obtained solution was washed with H2O (2 × 15 mL), dried over Na2SO4, and evaporated. Ozonolysis in a mixture of acetic acid and dichloromethane. By method b after chromatographing 1.86 g of residue (SiO2, petroleum ether-tert-butyl methyl ether, 2 : 1) we obtained 0.60 g (75%) of nonanoic acid 3 and 0.64 g (74%) of nonanedioic acid 2, whose IR, 1H and 13C NMR spectra were identic to those previously described [17].
64%; 35%
With ozone; In carbon dioxide; at 15 - 140℃; under 48754.9 - 165017 Torr; for 0.416667h;Autoclave;
(Reference Example 11)An oxygen-containing compound was produced using a batch reaction process.First, oleic acid (0.565 g, 2.00 mmol) was added to a 50 mL stainless steel autoclave, and 28 g of a high-pressure carbon dioxide solution of high-purity ozone containing 2.7 mmol of ozone was supplied from an ozone supply device to give 6.5 MPa at 15C.After stirring for 10 minutes, the temperature was increased to 140C to give 22 MPa, and stirring while heating was conducted for 15 minutes.After the reaction, the autoclave was cooled with ice, and the pressure was reduced; subsequently, the contents were treated with diazomethane, and the reaction mixture was analyzed by gas chromatography using biphenyl as an internal standard. The results confirmed that azelaic acid was obtained in a yield of 64%, and nonanoic acid was obtained in a yield of 35%.
51.5 - 52.7%
With ozone;zeolite activated with manganese; at 95℃;Product distribution / selectivity;
Example 1; Oxidative Ozonolysis of Oleic Acid; A micro falling-film reactor was used for the first part of the reaction, the reaction of ozone and oleic acid. The system consisted of 64 channels with a channel width and a channel depth of 300 mum and a channel length of 75 mm. The channels were operated in parallel and were etched through for educt input and product removal. The cooling channels corresponded in their diameter to the reaction channels. By virtue of the construction of the microreactor, contact between gas and liquid took place solely in the cooled region. The reaction was carried out in countercurrent, although co-current operation is also possible. Technical oleic acid with the following composition was used for the ozonolysis: 5% palmitoleic acid (C16:1-FA), 69% oleic acid (C18:1-FA), 13% linoleic acid (C18:2-FA), 1% linolenic acid (C18:3-FA) and 1% gadoleic acid (C20:1). The other constituents were generally fatty acids with a chain length of C12 to C20. To dilute the reactants, the technical oleic acid was mixed with pelargonic acid in a ratio of 1:2. Owing to their instability, the ozonization products were directly reacted and cleaved with oxygen in microreactors. In such a fixed-bed microreactor consisting of 50 parallel, 70 mm-long reaction channels, with a diameter of 600 mum, with 25 mum thick filters at the outlet of the microchannels, providing for retention of the catalyst powder, having particle diameters of 50 to 80 mum, using zeolite activated with manganese, as described in International Published Application WO 95/21809 A1, the reaction was carried out at 95 C., the reactor being heated with thermal oil. In view of the residence time required, two reactors of this type were arranged in tandem. The reactors for the second reaction step were operated in co-current (trickle flow) with oxygen, the mass ratio between ozonization products and oxygen being adjusted to 90:10. However, countercurrent operation is also possible. In all tests, ca. 0.3 Nl/h oxygen was used per reactor. The heat of reaction was dissipated through the thermal oil. Both reaction steps were carried out continuously. The first reaction step took place at 20 C. 0.1 ml/min. of the liquid fatty acid mixture was used. The quantity of starting gas was varied according to the ozone concentration and the unreacted ozone was catalytically destroyed. The ozonolysis of technical oleic acid was carried out in the first microreaction system. In the second microreaction system, the ozonization products formed were cleaved under the effect of oxygen to form a mixture, with the principal constituents being azelaic and pelargonic acid. The results are set out in Table 1 (recording the mean values of three measurements). The yield of azelaic acid is based on the total input of the technical oleic acid used, i.e., including the saturated constituents. The volume/time yield is based on the empty volumes of the reactors used. The reaction mixture was analyzed by GC. Only minute traces of oleic acid were detected, so that the conversion under the selected conditions in the first reaction step can be regarded as a full conversion. After leaving the second oxidation reactor, ozonides could no longer be detected either. To monitor the GC analyses, relatively large quantities, from repeated test runs, were worked up as follows: the pelargonic acid was first distilled off and the azelaic acid was extracted with water and crystallized, yellowish crystals being obtained. After a recrystallization step, white crystals were obtained. The melting point was between 103 and 105 C., i.e., close to that of pure azelaic acid. GC analysis revealed purities of 97to 99%. The yield of azelaic acid, based on the quantity of technical oleic acid used, was between 51.5 and 52.7% of the theoretical and, by virtue of the excellent dissipation of heat, was almost independent of the ozone concentration in the starting gas. The yield, and hence the selectivity, for azelaic acid exceeded those of conventional processes for the selected starting composition. TABLE 1 Test results (variation of the ozone concentration in the first reaction stage, oxidation under identical conditions at 95 C. in a fixed-bed microreactor) Parameter 1 2 3 4 5 Ratio of oleic to 1:2 1:2 1:2 1:2 1:2 pelargonic acid [kg/kg] Starting fatty acid 0.1 0.1 0.1 0.1 0.1 [ml/min] c(ozone) in the starting 2 5 7 10 13 gas [%] Starting gas [NI/h] 8.5 3.4 2.4 1.7 1.3 Temperature [ C.] 20 20 20 20 20 Pressure [bar] 1.3 1.3 1.3 1.3 1.3 Residence time [s] 120 120 120 120 120 Yield of azelaic acid [%] 51.5 52.1 52.5 52.7 52.3 Volume/time yield 1.12 1.13 1.14 1.14 1.13[t · h-1 · m-3]* Volume/time yield 0.26 0.26 0.27 0.27 0.27[t · h-1 · m-3]** *Yield of azelaic acid, based on the volume of the falling-film absorber **Yield of azelaic acid, based on the volume of the falling-film absorber and the two following oxidizers
With dihydrogen peroxide; ortho-tungstic acid; In water; at 70℃; under 760.051 Torr; for 6h;
0151] The tests described below illustrate the reaction for oxidation of oleonitrile (ON) and also, by way of comparison, that of oleic acid (OA) and of methyl oleate (MO) by means of aqueous hydrogen peroxide, of varying the reaction parameters, i.e. the H2O2 content of the solution injected, and the injection molar ratios and flow rates, at a constant set temperature (70 C.) and under atmospheric pressure. [0152] 100 g of fatty compound and 1.1 g of tungstic acid (H2WO4; Merck 98%) are introduced into a 250 cm3 jacketed reactor comprising a mechanical stirrer, and then stirred and heated at 70 C., said temperature being maintained by circulation of thermostatic water. The aqueous hydrogen peroxide is then added in weight contents which are variable according to the tests, via a peristaltic pump at variable addition speeds according to the tests. The reaction is stopped after 6 h, the aqueous phase is separated for analysis. The remaining organic phase is washed several times with hot water until aqueous hydrogen peroxide has disappeared from the washing water. [0153] The fatty substrates introduced come from the following sources: The fatty substrates introduced come from the following sources: [0154] oleonitrile (ON): Arkema with C16:0: 3%, C18:0: 9.7%, C18:1: 84.7%, C18:2: 1% (% by weight). [0155] oleic acid (OA): Oleon Radiacid 0210 (C18:1: 72%, C18:2: 9% by weight) [0156] methyl oleate (MO): Aldrich Grade Technique (C18:1: 70% by weight) [0157] The operating conditions and the results obtained are given in table 1 hereinafter, in which ?molar ratio? denotes the H2O2/fatty compound molar ratio and NA denotes the presence (Y) or the absence (N) of nonanoic acid, characteristic of the cleavage of the molecule. [TABLE-US-00001] TABLE 1 operating conditions and results Exam- Flow Initial Final ple [H2O2] Molar rate iodine iodine No. Substrate (%) ratio g/min value value NA 1 ON 50 6 0.24 98 4 Y 2 ON 50 4 0.48 98 30 Y 3 ON 50 6 0.48 98 41 Y 4 ON 35 4 0.34 98 37 N 5 ON 50 4 0.48 98 32 Y 6 MO 35 1.8 0.128 91 74 N 7 MO 50 4 0.48 91 80 N 8 MO 50 4 0.48 91 87 N 9 OA 35 1.8 0.128 86 9 N 10 OA 50 2.7 0.5 86 9 Y 11 OA 35 1.8 0.256 86 33 N 12 OA 50 6 0.48 86 26 Y [0158] The oleonitrile oxidation reaction makes it possible to substantially reduce the iodine value of the medium (see example 1) marking the disappearance of the double bonds (formation of diols or cleavage). The H2O2 concentration has an influence on the cleavage of the molecule treated (compare examples 1, 2, 3 and with example 4) resulting in heminitrile formation. [0159] The methyl oleate oxidation reaction results only in a very low conversion of the double bonds regardless of the operating conditions. This oleic acid derivative is not therefore suitable for the formation of diacids by oxidative cleavage. [0160] The oleic acid oxidation reaction allows a reduction in the iodine value of the medium (examples 9 to 12) and the formation of diacids, with a suitable H2O2 concentration.
With tungstophosphoric acid *15.4 H2O; cetylpyridinium chloride; dihydrogen peroxide; In water; at 85℃; under 760.051 Torr; for 5h;
EXAMPLE 1 In Situ Preparation of the Phase-Transfer Catalyst In a method of oxidative molecular cleavage of a fatty compound and of preparation of carboxylic acids (especially azelaic acid (COOH-(CH2)7-COOH) and pelargonic acid (CH3-(CH2)7-COOH)) according to the invention, a fatty acid composition comprising oleic acid is first prepared from a sunflower oil having a high content of oleic acid (ARTERRIS, Toulouse, France). Enzymatic hydrolysis of the sunflower oil is carried out, during which 22.5 kg of sunflower oil are placed in contact with a solution of a lipase (Lyven, Colombelles, France) of Candida cylindracea in distilled water (20.1 kg) with magnetic stirring at 40 C. for 5 hours. A fatty acid preparation is formed, the composition of which, determined by gas chromatography, is given in Table 1 below.TABLE 1 Fatty acid Composition by mass, % Oleic acid, C18:1 87.6 Linoleic acid, C18:2 4.7 Palmitic acid, C16:0 3.5 Stearic acid, C18:0 3.1 Capric acid, C10:0 0.2 Others 0.9 21 g of this fatty acid preparation comprising 65 mmol of oleic acid are placed in a 250 ml three-necked round-bottomed flask equipped with a cooler, a mechanical stirrer and a heating device. There are added dropwise 2 ml of an aqueous solution of a quaternary ammonium salt (3.36 mmol) selected from the group formed of tetrabutylammonium chloride (n-Bu4NCl, Sigma Aldrich, Saint-Quentin Fallavier, France), tetrabutylammonium bromide (n-Bu4NBr, Sigma Aldrich, Saint-Quentin Fallavier, France), N-cetylpyridinium chloride monohydrate (C5H5N(n-C16H33)3Cl, H2O, Sigma Aldrich, Saint-Quentin Fallavier, France), N-methyl-N,N,N-trioctylammonium chloride (CH3N(n-C8H17)3Cl, Sigma Aldrich, Saint-Quentin Fallavier, France), which is better known by the name "aliquat 336", and N,N,N,N-tetraoctylammonium chloride (N(n-C8H17)4Cl, Sigma Aldrich, Saint-Quentin Fallavier, France). An emulsion of the oleic acid and the solution of the quaternary ammonium salt is formed by mechanical stirring of the resulting mixture.There are prepared by mixing and stirring at ambient temperature for 30 minutes 4 g (1.2 mmol) of tungstophosphoric acid (H3PW12O40.15.4H2O) and 34 ml of 30% oxygenated water (325.0 mmol) in 5 ml of distilled water. The solution of tungstophosphoric acid is added to the emulsion of the oleic acid and the quaternary ammonium salt. The addition of the solution of tungstophosphoric acid to the three-necked flask containing the emulsion is carried out dropwise over a period of 5 minutes. After addition of the solution of tungstophosphoric acid to the emulsion, the reaction mixture is heated to a temperature of 60 C. The reactor is placed and maintained under mechanical stirring (400 rpm) at a temperature of 85 C. and at atmospheric pressure for a period of 5 hours, and the reactor is then allowed to cool to ambient temperature again. The pH of the reaction mixture is adjusted to a value of pH=1 by addition of one volume of an aqueous solution of hydrochloric acid at a concentration of 4 mol/l.In order to separate the carboxylic acids formed and the catalyst, one volume of ethyl acetate is added to the acidic mixture at pH=1 and then the reaction mixture is placed at a precipitation temperature (Tprecip, ambient temperature or temperature below 4 C.) so as to form a precipitate of the catalyst. The precipitate formed is washed with ethyl acetate. The aqueous phase containing the salts is separated from the organic phase in a separating funnel and is then washed with ethyl acetate. The different organic phases are combined, dried over ammonium sulfate and evaporated under reduced pressure.The samples obtained are analyzed and quantified by gas chromatography by means of a Varian chromatograph coupled to a flame ionization detector (FID) and equipped with a capillary column (L 50 m, 0.25 mm, particle size 25 -m) for analysis of the fatty acid methyl esters. The mobile phase is helium (Air liquide, France) at a pressure of 1034 hPa (15 psi) at the head of the capillary column. The temperature of the injector and of the detector is 250 C. The temperature of the oven containing the column is maintained at 100 C. for 5 minutes and is then increased gradually to 180 C. at a rate of 5 C./minute over 10 minutes and is finally increased gradually to 250 C. at a rate of 10 C./minute over 5 minutes and maintained at that temperature for 43 minutes.For the purposes of analysis, a solution of each sample is prepared at a concentration of 10 mg/ml in methyl tert-butyl ether (MTBE). The fatty acids are converted into methyl esters by treatment with trimethylsulfonium hydroxide. Pentadecanoic acid at a concentration of 2 mg/ml is added as internal standard. The results are presented in Table 2 below, in which Tprecip is the precipitation temperature, AZA % and PEA % represent the value of the synthesis and extraction yield of azelaic acid and pelargonic acid, respectively, relative to the starting oleic acid.TABLE 2 PEA, Catalyst prepared in situ Tprecip AZA, % %...
With dihydrogen peroxide; at 70℃;
The reaction for the oxidative cleavage of oleic acid is performed in a similar manner to that for the oxidative cleavage of oleonitrile (replacement with oleic acid). The oleic acid used is Oleon at a purity of 75%. The reaction takes place at 70 C. without a stream of air and with 144% pure H2O2 relative to the pure oleic acid. Table 5 below gives the composition of the oleic acid cleavage solution and its extract with 58/42 acetic acid (AA)/water (weight ratio).
91%Chromat.; 69%Chromat.
With dihydrogen peroxide; ortho-tungstic acid; In water; for 8h;Reflux;
In a 250-mL round-bottom flask equipped with a condenser, tungstic acid (0.283 g, 1.13 mmol) was suspended in aqueous solution of H2O2 (60 % w/w, 51.2 g,904 mmol) and the system was stirred at 343 K. Oleic acid (36.3 mL, 113 mmol) was added as soon as complete dissolution of tungstic acid was observed. The reaction mixture was stirred under reflux. After 8 h, the mixture was allowed to cool down to room temperature and cool water (50 mL) was added. The reaction mixture was extracted with hot ethyl acetate (4 × 100 mL). The combined organic layers were dried with anhydrous sodium sulfate and evaporated under reduced pressure. The products were analyzed by 1H NMR without further purification of the crude material and by GC after derivatization (tr AA = 11 min, tr PA = 4.2 min, tr DSA = 20 min).
The 80 g oleic acid and 240 g glacial acetic acid ratio is 40 C in water bath, and inject the ozone reaction 6 hours, to obtain the oleic acid ozonides; wherein ozone by the ozone generator access to the reaction system, the ozone generator power is 50 W, into the ozone generator of the oxygen flow rate is 1.5 L/min; To the obtained oleic acid ozonide oxygen is filled in, the reaction temperature is 120 C, the reaction time is 3 hours, wherein the oxygen flow rate is 0.4 L/min, to obtain the oxidative cleavage product; The obtained for oxidative cleavage product 800 ml 95 C near-boiling water extraction; Extracting the delaminated, oil phase into the reduced pressure distillation, vacuum distillation of steam when the temperature is 120 - 130 C, to obtain 13.5 g crude [...], the purity is 72%; The aqueous phase into the 0 - 5 C refrigerator crystalline 24 hours, filtering, 50 C vacuum dry 24 hours, the obtained unsaturated fatty acid by crude 31.3 g, purity is 90%; the obtained unsaturated fatty acid by the use of the crude product of the 200 ml 90 C near-boiling water to re-crystallization twice, to obtain the pure product of unsaturated fatty acid by 9.4 g, purity of 97%.
Stage #1: Adipic acid; 2-butyl-2-ethylpropane-1,3-diol; nonanoic acid at 200 - 220℃; for 7h;
Stage #2: With triethylamine at 80℃; for 3h;
Yield
Reaction Conditions
Operation in experiment
Stage #1: 1,10-decanedioic acid; 2-butyl-2-ethylpropane-1,3-diol; nonanoic acid at 200 - 220℃; for 7h;
Stage #2: With triethylamine at 80℃; for 3h;
32
[ 112-05-0 ]
[ 72235-52-0 ]
[ 816465-08-4 ]
Yield
Reaction Conditions
Operation in experiment
93%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 20℃;
Example 2; (2S)-3-(4-{2-[(2,4-difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid; (i) N-(2,4-Difluorobenzyl) nonanamide; To a solution of <strong>[72235-52-0]2,4-difluorobenzylamine</strong> (0.47 g, 3.3 mmol) in methylene chloride (30 ML) were added nonanoic acid (0.52 g, 3.3 mmol) and DMAP (0.40 g, 3.3 mmol) followed by l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.67 g, 3.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HC1 (3 x 75 ML), aqueous NAHCO3 (75 ML), and brine (75 ML) and dried over anhydrous NA2SO4. CONCENTRATION IN VACUO afforded 0.87 g (93%) of an oil, which solidified upon standing. H NMR (600 MHz, CDCl3) : 80. 80-0.86 (m, 3H), 1.16-1. 28 (m, 10 H), 1.53-1. 62 (m, 2H), 2.11-2. 17 (m, 2H), 4.37 (d, 2H), 6.12 (bs, 1H), 6.70-6. 81 (m, 2H), 7.27 (m, 1H).
Stage #1: trioleoylglycerol; trilinolenin With ozone In water at 27℃; for 5h;
Stage #2: With hydrogen In tetrahydrofuran at 20 - 135℃; for 5.5h;
2.A; 2.B; 2.C; 2.D; 2.E; 2.F
Example 2: Preparation of Polyols from Canola Oil (GII-Polyol); Ozonolysis Reactor; [00297] The reactor 10 presently disclosed offers an improvement over prior art ozonolysis vessels, such as those utilized by Lin, S. H. and Wang, C. H. (Industrial wastewater treatment in a new gas-induced ozone reactor, Journal of Hazardous Materials *** 295-309,(2003)) illustrated in Figure 41 (Prior Art). The reactor of the present invention is fed with a motor 28, such as a Direct Current Permanent Magnet 1 HP Motor from Leeson electric-corporation, USA. The water, which temperature is controlled by a chiller, is rushed into the outer layer 14 of the reactor (entry labelled "H2O in"; 16), circulated around the reaction vessel 12 and evacuated (labelled "H2O out"; 18). The water is kept flowing during the reaction to keep the reaction system at a constant temperature. Ozone is generated in an ozone generator (such as Azcozon Model RMV16-16 from Azco Industries Ltd, Canada) with oxygen or air as the feed gas, and introduced into the reactor from the two apertures for ozone input at opposing ends of an ozone inlet channel 24 (the apertures being labelled as "O3, O2 in" (20) and "O3, air in" (22) in Figure 39). The ozone inlet channel 24 is disposed at the lower end of the reaction vessel 12 and extends across the diameter thereof. The gas is released from the ozone inlet channel 24 into the reaction vessel 12 through a plurality of pores 26, which are evenly spaced across the length of the ozone inlet channel 24. The nonreturn valves 36 prevent backflow of the reaction solution to the two apertures for ozone input (20, 22) and the aperture for nitrogen input, 38.[00298] The two apertures for ozone input, 20 and 22, and the pores 26 in the ozone inlet channel 24, provide for substantially uniform distribution of ozone throughout the reaction vessel 12. This improved distribution of ozone increases the effectiveness of the ozonolysis reaction, allowing for shorter reaction times, higher reaction temperatures, and increased homogeneity of end products. This arrangement differs from prior art ozonolysis vessels, such as the embodiment illustrated in Figure 41, which only have a single aperture for ozone input. [00299] The magnet motor 28 is connected to a longitudinally disposed agitator 30 which extends into the reaction vessel 12. The motor 28 is kept rotating at high speed during the reaction. The agitator 30 comprises a plurality of pitched blades 32, which may be fixedly mounted or releasably mounted to the agitator 30 by means known to those skilled in the art. In one embodiment, the blades 32 may be welded to the agitator 30. In one embodiment, the blades 32 are trapezoidal in shape, which reduces the resistance. In another embodiment, the blades 32 are attached to the agitator 30 at an angle of from about 30 degrees to about 60 degrees. Such an angle of attachment has been found to reduce vortex formation and increase the rate of reaction. In yet another embodiment, the blades 32 contain a plurality of holes 34, which increase contact areas between the reagents and further reduce vortex formation. Figures 40(a) and 40(b) illustrate the blades 32. in greater detail in accordance with one embodiment of the invention. The plurality of pitched blades are oriented such as to direct the contents of said reaction vessel downward toward the ozone inlet channel.[00300] Thus, in the reactor vessel of the current invention, the apertures for ozone input 20 and 22, the ozone inlet channel 24, the pores 26 within the ozone inlet channel 24, as well as the rotating blades 32 have been designed to ensure thorough contact and full reaction of ozone with the starting material.[0030I]In one embodiment, the blades 32, agitator 30, and reaction vessel 12 may be made of stainless steel, such as SS 316 L.[00302] Li one embodiment of the present invention, the reactor has the following characteristics, which are presently described by way of example and should not be interpreted as limiting. It has been found that a reaction vessel 12 having a volume of 1727 cm3 (diameter = 10 cm; height = 22 cm) can accommodate 200 g of starting material (vegetable oil) in 1000 mL of solvent. The ozone inlet channel 24 comprises twelve pores 26 evenly spaced at 0.8 cm apart, wherein the pores have a diameter of 0.8 mm. The agitator 30 has six blades 32 having the dimensions illustrated in the embodiment shown in Figure 40(a), and the blades 32 contain six holes 34 having a diameter of 0.3 cm. The angle of attachment of the blades 32 to the agitator 30 can vary from about 30 degrees to about 60 degrees. The blades 32,. agitator 30, and reaction vessel 12 are made of SS 316 L.; Step A - Ozonolysis; [00303] Canola oil (10Og) and deionized water (40Og) were poured into a specially designed reactor (schematic shown in Figure 39 and described above). The reaction was performed at 270C, at 5 L/min O2 flow rate and 80 rpm agitation rate. After 5 hours, the ozone generator was stopped and the reaction vessel was purged with N2 for 10 minutes to remove the unreacted ozone from the vessel. 400ml of tetrahydrofuran (THF) was then added into the vessel to dissolve the ozonide product. The product was then transferred to a separatory funnel where the organic part was collected for the hydrogenation step.; Step B - Hydrogenation; [00304] 10.5 g of Raney nickel catalyst were added to the ozonide (490.8g) in THF in a hydrogenation vessel (2L, Parr Instrument Co, USA) fitted with a magnetic drive. The reaction vessel was flushed 3 times with nitrogen at 200 psi pressure to remove the air and then was charged with hydrogen gas at 350 psi at room temperature. The temperature was increased over 30 minutes to 1350C with a concomitant increase in pressure to 520 psi. The hydrogenation reaction was carried for 5 hours at this temperature and the pressure decreased with the consuming of hydrogen. The temperature was then reduced to room temperature with cooling water and to a final pressure of 290 psi. The unreacted hydrogen gas was removed from the reaction vessel with nitrogen gas. The remaining mixture was filtered over Celite and the aqueous layer removed in a separatory funnel[00305] To insure complete hydrogenation of the double bonds and ozonolysis products, the above procedure was repeated on the remaining organic material from the separatroy funnel. The final hydrogenation product was kept for distillation.; Step C - Gas Chromatography (GC); [00306] To determine the amounts of short chain compounds present as by-products from the hydrogenation reaction, a Varian 3500 Capillary Gas Chromatograph equipped with a Flame Ionization Detector (GC-FID), a Varian 8200 Auto Sampler and a BP20025 column (30-m long, 0.25-mm internal diameter, and 0.25-μm thick silica wall) was used. The system was controlled with Varian' s "Star Chromatography Workstation" software V.5.51. The injector and the detector temperature were fixed at 250°C. The temperature of the column initially set at 50°C was increased to 250°C in two successive steps: from 500C to 9O0C at a rate of 25°C/minute and from 900C to 2500C at a rate of 10°C/minute.; Step D - Wiped- blade Molecular Distillation; [00307] The solvent was removed on a rotary evaporator (Heidolph Laborota 4001, UK) to yield a viscous yellow oil. GC analysis showed that the removed THF was 100% pure and no product was also removed with THF. The wiped blade molecular distillation unit (Model VKL 70/ICL-04, from rncon Processing) was set up at a jacket temperature of 1150C, and the temperature of the condenser 3O0C. The pressure of the distillation system was reduced to 20 mTorr and the viscous oily product added into the distillation system through an addition funnel at a speed of lmL/min. After all the product had been added to the distillation system, the unit was kept running for 30 minutes, to allow the complete collection of the residue and distillate. Finally, distillate (31.Ig) and residue (47.Og) were obtained. The distillate fractions from the flash evaporator and distillation were analyzed by GC, and the residue fraction analyzed by HPLC.; Step E - Flash Chromatography; [00308] A column of dimensions 3 id x 30cm was packed with 40Og (about 212 mL volume) of silica gel (230-400 mesh). Material from the residue fraction of distillation (4.3g) was added. The column was then eluted under air pressure with gradient flow phase composed of hexane and ethyl acetate. The ratios (v/v) of hexane to ethyl acetate was started with 50:1, then gradually decreased to 20:1, 17:1, 10:1, 8:1, 5:1, 3:1, 2:1, 1:1, followed by 1 :2, 1 :3, 1 :4. Finally pure ethyl acetate was used and the fractions were collected in 30mL-test tubes. Ratios of flow phase of 20:1, 8:1, 2:1 and 1:4 were used on fractions 28-50, 131-143, 264-289, and 366-389 respectively. Thin layer chromatography (TLC) was run on each fraction using hexane and ethyl acetate as the developing system with ratios (v/v) of hexane and ethyl acetate of 3:1, 2:1, and 1:1. The glycerides and related compounds were detected by spraying the plates first with methanol containing 10% sulphuric acid (concentration 98%) and then heating them at 2000C for 5 minutes.; Step F - High Performance Liquid Chromatography (HPLC); [00309] The HPLC analysis protocol used was a modification of the procedure developed by Elfman-Borjesson and Harrod (Elfman-Borjesson, I. and M. Harrod, Analysis of Non-Polar Lipids by HPLC on a Diol Column. J. High Resol. Chromatogr. 20: 516-518 (1997)) for analysis of lipid derivatives. The HPLC system consisted of a dual Milton Roy pump with a 20 μL auto-injector. The column was packed by Betasil Diol-100 (5 μm particle size) 250x4 mm produced by Thermo Hypersi-Keytone and maintained at 5O0C with a Biorad column heater. The detector was an Alltech EDSL 2000 evaporative light scattering system maintained at 1000C with a gain setting of 10 (on the 12 unit scale) and a nitrogen pressure of 2 bar. Two solvents were connected to the pump as the mobile phase. A was 100% heptane and B 50% heptane with 50% isopropyl alcohol (IPA). A run consisted of a linear gradient of 100% A to 83% A and 17% B in 30 min; then back to 100% A in 1 minute at a flow rate of 3 mL/min.
Stage #1: trioleoylglycerol; trilinolenin With ozone In water at 0℃; for 8h;
Stage #2: With hydrogen In tetrahydrofuran at 130℃; for 8h;
3.A; 3.B; 3.C; 3.D; 3.E; 3.F; 3.G; 3.H
Example 3: Preparation of Polyols from Canola Oil and Flax Oil; [00310] Three grades of polyols were synthesized in this example: (i) polyols from canola oil using oxygen gas supply to generate the ozone, and referred to as canola- oxygen; (ii) polyols from canola oil using air supply to generate the ozone, and referred to as canola-air; and (iii) polyols from flax oil using air supply to generate the ozone, and referred to as flax-air.; Step A - Ozonolysis; [00311] The preparation of polyols from canola and flax was generally conducted as set out in the previous examples above. Briefly, the polyols were synthesized by ozonolysis of the vegetable oils followed by hydro genation in the presence of a nickel catalyst. The ozonolysis was carried out in a reactor fed with ozone gas generated by a Model-RMU 16-16 generator from Azco Industries Ltd supplied either with air or oxygen. The hydrogeriation was completed in a Parr-Pressure Reaction Apparatus (Parr Instrument Company Inc). The vessel temperature of the hydrogenator was controlled by a 4835- Parr controller. The distillation was carried out in a Model VKL 70/ICL-04 wipe-blade molecular distillation system from Incon Processing. The procedure was as follows: 100 g of triacylglycerol oil was mixed with 400 ml of de-ionized water in a high speed mixer and the mixture sonicated for 1 hr in a Sonic 300-Dismembrator sonicator at full power. The resulting solution was agitated at 500 rpm in the ozonolysis reactor vessel until the temperature of the vessel stabilizes at 0 0C. This step took about 45 minutes to complete. The ozone generator was then supplied with air or oxygen at a constant flow rate of 5 L/min. The ozonolysis reaction was started by directly introducing the generated ozone gas in the reactor with the solution still agitated at 500 rpm. After about 8 hours, the water was removed and THF (or another suitable solvent) was added. The resulting solution was then transferred to the hydrogenation reactor where the reaction was carried out at 130 °C under pressure of 600 psi for about 8 hours. After the removal of the catalyst and the solvent, the hydrogenated crude was transferred to a wiped blade molecular distillation system to remove the short-chain by-products - i.e. the products were separated into a light fraction and a heavy fraction (polyols).; Step B - FTIR; [00312] The spectra were collected on a Nicolet Magna 750 spectrometer system, equipped with a room temperature MCT-B detector. The liquid samples were analyzed neat as a thin film between two KBr plates. The thickness of the film was manually adjusted to ensure that no peak absorbance was over 1.0 absorbance units. The spectra were recorded in the range 400-4000 cm"1 with a nominal resolution of 4 cm"1. A background spectrum of the clean, dry plates was first collected before each absorbance spectrum and 32 interferograms were co-added before Fourier transformation using Nicolet Ormiic software.; Step C -GC; [00313] To determine the amounts of short chain compounds present as by-products of the ozonolysis and hydrogenation reactions, a Varian 3500 Capillary Gas Chromatograph equipped with a Flame Ionization Detector (GC-FID), a Varian 8200 Auto Sampler and a BP20025 column (30-m long, 0.25-mm internal diameter, and 0.25- μm thick silica wall) was used. The system was controlled with the Varian "Star Chromatography Workstation" software V.5.51. The injector and the detector temperature were fixed at 250 0C. The temperature of the column initially set at 50 °C was increased to 250 °C in two successive steps: from 50 0C to 90 °C at a rate of 25 °C/minute and from 90 °C to 250 0C at a rate of 10 °C/minute.; Step D -HPLC; [00314] The molecular profile of the polyol products were obtained with a HPLC system using a modified procedure by Elfman-Borjesson and Harrod (11) for analysis of lipid derivatives. The HPLC system consisted of a dual Milton Roy pump with a 20 μL auto- injector. The column was a Betasil Diol-100 (5 μm particle size) 250 x 4 mm produced by Thermo Hypersil-Keystone and maintained at 50 0C with a Biorad column heater. The detector was an Alltech EDSL 2000 evaporative light scattering system maintained at 100 °C with a gain setting of 10 (on the 12 unit scale) and a nitrogen pressure of 2 bar. Two solvents reservoirs were connected to the pump as the mobile phase. Solvent A was 100% heptane and solvent B was 50% heptane with 50% isopropyl alcohol. A run consisted of a linear gradient of 100% A to 83% A and 17% B in 30 min.; then back to 100% A in 1 minutes at a flow rate of 2 mL/min.; Step E - Rheometric Measurements; [00315] The viscosities of the polyol samples were measured in shearing mode with the Universal Dynamic Rheometer PHYSICA UDS 200 (Paar Physica USA) with a constant shearing rate of 51.6 s"1. The viscosities were recorded at 6 different temperatures, from 50 °C to 25 0C every 5 0C. The viscosities were also measured at 25 0C as a function of time.; Step F -DSC; [00316] The "TA 2920 Modulated DSC" system from TA Instruments was used to study the thermal transitions of the polyols. The data sampling and temperature control procedures were fully automated and controlled by the "TA Instrument Control" software program and the data were analyzed using the "TA Universal Analysis" software. The procedure to record the crystallization and melting curves was as follows: Initially the sample was kept at 20 0C for 5 minutes to reach steady state and then was heated to 80 °C with a rate of 5 °C/min to erase its thermal history. To record the crystallization curve, the sample was cooled down to -50 0C at a constant rate of 5 °C/min and kept at this temperature for 5 minutes to allow the completion of the crystallization. The sample was then heated to 80 0C at a constant rate of 5 °C/min to record the melting curve.; Step G - Refractometry; [00317] The refractive index of the materials was determined according to the ASTM method T>1A1- 99, with a CARL Zeiss (Germany) refractometer.; Step H - Hydroxyl and acidity values; [00318] The hydroxyl numbers of the polyols were determined according to the ASTM titration method D 1957-86 and the acidity values were determined according to the ASTM method D4662-98. Triplicate specimens were measured for each polyol and the average values and standard deviations are reported here.
With sulfuric acid; dihydrogen peroxide In water at 90℃; for 20h;
1
Example 1Oxidation reaction was carried out with the use of a catalyst system containing 30% hydrogen peroxide water (oxidant) (13.2 equivalents), sodium tungstate and hydrogen sulfate methyltrioctylammonium (0.15 equivalents each), sulfuric acid (0.37 mmol), and distilled water (1 ml) for triolein (1.0 g). As a result, the yield of nonanoic acid, which is monocarboxylic acid, was 87%. In addition, the yield of azelaic acid was 19%. The remaining product was triazelain when the reaction was terminated. Accordingly, it has been revealed that an oxidation reaction of triolein with hydrogen peroxide is a selective reaction, and that a reaction in which oxidation cleavage of an olefin portion results in generation of carboxylic acid proceeds in a preferential manner. The reaction formula is shown below.
General procedure: The chlorosilyl resin was swollen in dry DCM (20 mL) under argon atmosphere. A solution of imidazole (1.16 g, 17.0 mmol) and diol 5 (10.7 g, 16.8 mmol) in DCM (20 mL) was subsequently added. The mixture was vortexed overnight at room temperature using a Burrell wrist-action shaker. The loaded resin was washed with DCM (3 × 75 mL) and dried overnight under vacuum to provide 7.3 g of resin 6 (loading of 0.40 mmol/g). IR (KBr): nu 3442 (OH, alcohol), 1702 (C=O, carbamate) cm-1. The free diol 5 (8.7 g) was easily recovered after flash chromatography using EtOAc/hexanes (1:1) as eluent. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. To each of the resin-bound derivatives 8 was added 2 mL of an acid solution of 2 M methanolic HCl (AcCl + MeOH) in DCM (20:80, v/v) and the resulting suspensions were vortexed at 600 rpm for 1 h. DCM (1 mL) was added and the suspensions were filtered and the recovered filtrate was neutralized with 0.5 mL of 10% aqueous NaHCO3 (pH 8). The biphasic solution was filtered using a phase separator syringe (Biotage) and the resulting organic solution evaporated under reduced pressure. The 12 (3 × 4) crude amide compounds of library A (Table 2 ) were purified by filtration over a silica gel plug (10 mL) using EtOAc/hexanes (1:1) (15 mL) and then EtOAc (20 mL). In another experiment, the 28 (4 × 7) amide compounds of library B (Table 3 ) were evaporated to dryness and judged sufficiently pure by TLC and 1H NMR analyses for direct screening on HL-60 cells. All members of libraries A and B were analyzed by TLC, 1H NMR and LRMS.
With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 4 - 20℃; for 24.0h;
General procedure: PPT (500 mg) and different fatty acids (butyric acid, n-pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, capric acid, lauric acid, oleic acid, 8 mmol respectively) were dissolved in 25 mL dry tetrahydrofuran. N,N?-dicyclohexylcarbodiimide (DCC, 8 mmol) and 4-dimethylaminopyridine (DMAP, 0.8 mmol) were added while cooling on ice (4C). The mixture was stirred at room temperaturefor 24h, then was filtered, washed with CHCl3 three times and the filtrate combined. The filtrate was was evaporated to dryness under 80C to obtain the crude product. The crude product was subjected to silica gel column (3cm×40cm) chromatography, eluted with a gradient of petroleum and acetone (10:1-1.1) to obtain other compounds respectively.
With copper(II) ferrite; oxygen; In neat (no solvent); at 80℃; under 18751.9 Torr; for 5h;Autoclave;
16.0020 g of crude diol and 0.1631 g of CuFe204 prepared in this way were charged into an autoclave pressurised with 25 bar of 02. The autoclave was held at a temperature of 80C for 5 hours with stirring at 500 rpm. (0104) At the end of the reaction time the catalyst was separated from the oily phase by centrifuging at 4500 rpm for 10 minutes. (0105) Under these operating conditions 2.76 g of pelargonic acid and 4.40 g of azelaic acid were obtained, corresponding to an approximate yield by weight of 46.65% of pelargonic acid and 57.24% of azelaic acid with respect to what could be theoretically obtained.
General procedure: This embodiment provides a preparation method of decanoyl vanillamine, which specifically comprises the following steps1) Take a 100ml reactor, install a water separator (with a condenser),Magnetic stirrer and thermometer; in the reactorAdd vanillin free base,nonanoic acid,SiO2-H3BO3 catalyst and toluene.2) Stirring,Heating to reflux water separation reaction 6h~10h,Then cooled to 30 C,Take a small amount of the reaction solution to remove the solvent under reduced pressure.HPLC analysis.3) The remaining reaction solution is sequentially diluted with dilute hydrochloric acid having a mass concentration of 1%.After washing with pure water,The solvent is removed under direct reduced pressure until no liquid flows out.-5C cooled crystals.5) Filtering,A small amount of toluene washed the filter cake to give a white solid.After drying, the decanoyl vanillamine product is obtained.
87.4%
With boric acid; In toluene; at 130℃; for 8h;
In a three-neck 500 mL flask, 30.0 g (0.196 mol) of vanillin was added.31.0 g (0.196 mol) of n-decanoic acid and 300 mL of toluene were added.Boric acid 0.6g (9.8mmol), a three-neck flask fitted with a thermometer,A mouth water separator + reflux condenser (the water separator is loaded into the reaction flask,Then install the reflux condenser above the water separator.)Another mouth is closed, stirring is started, and the temperature is raised to 130C for 8 hours.After the reaction is completed, it is cooled to room temperature.Add 50mL of water twice to wash (extract boric acid),After drying over anhydrous sodium sulfate,Recovery of toluene under reduced pressure at 60 C using a rotary evaporatorTo the distillation of toluene is 2/3 of the original volume, stop decompression recovery,The remaining liquid is transferred to the cryogenic reactor,Stir and crystallize at -20C for 3h, filter,The resulting crystals are washed with toluene.Drained to give 50.3 g of a white powdery solid with a yield of 87.4%.HPLC purity 99.1%.White powder solids analysis:
74%
With Candida antarctica lipase B; In toluene; at 80℃; for 36h;Inert atmosphere; Molecular sieve; Enzymatic reaction;
A microwave-vial containing a solution of 1 (0.2 mmol, 1.0 equiv.), ammonium formiate (37.8 mg, 0.6 mmol, 3.0 equiv.) and Pd-catalyst(Pd-AmP-MFC, 13.4 mg, 0.01 mmol, 8 wt%, 5 mol%) or(Pd-CPG, 569A, 74.0 mg, 0.013 mmol, 6.6 mol%) in toluene (1 mL) under ISfc conditions was stirred at 80C for the time shown in Table 3. Afterwards, molecular sieves 4A, acid 4 (0.2 mmol, 1.0 equiv.) and lipase (120 mg/mmol) were added to reaction mixture and stirred at 80C for 36h. The crude reaction mixture was filtrated through Celite using CHCb(10 mL) as eluent and evaporated. The crude material was purified by silica gel flash column chromatography to afford the corresponding amide 3 as indicated in Table 3. The lipase is preferably Novozyme-435 immobilized on a macroporous anionic resin.
52%
With lipase; In tert-Amyl alcohol; at 45℃; for 48h;Molecular sieve; Enzymatic reaction;
The dried crude reaction mixture from the previous step (containing vanillylamine 94 mg, 0.62 mmol, 1.00 equiv.) was dissolved in 2-methyl-2-butanol (31 mL, 20 mM). To the reaction was added Ms 4A (2 g), compound 5b (98.7 mg, 0.62 mmol, 1.00 equiv.) and lipase (1.9 g, 20 mg/niL). The reaction was stirred at 45C for 48 h. Afterwards the reaction was cooled to room temperature and filtered. The solvent was removed under reduced pressure and the crude material was purified by chromatography to afford nonivamide (7b) (isolated yield 52 %) as light yellow oil.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; for 6h;
Into 10 mL of chloroform were dissolved 75 mg (0.2 mmol) of <strong>[26687-82-1]arctigenin</strong> and 31.6 mg (0.2 mmol) of nonanoic acid. Thereto were added 76.68 mg (0.4 mmol) of the water-soluble carbodiimide and 48 mg (0.4 mmol) of DMAP. In chloroform, the reactive components were caused to react with each other at room temperature for 6 hours. Water was added to the reaction liquid, and this system was stirred. The resultant organic layer was then washed with 1 N HCl, and a saturated solution of NaHCO3 in water. The chloroform layer was distilled off under a reduced pressure to yield 60.3 mg (yield: 58.7%) of <strong>[26687-82-1]arctigenin</strong> nonanoate. Mass analysis: ESI-MS/MS, m/z; 513.2 (M+H)+; Molecular formula: C30H40O7; 6.92 (d, 1H), 6.76 (d, 1H), 6.73 (d, 1H), 6.67 (dd, 1H), 6.53 (dd, 1H), 6.49 (d, 1H), 4.16 (dd, 1H), 3.90 (dd, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.75 (S, 3H), 2.97 (m, 2H), 2.54-2.63 (m, 6H), 1.75 (q, 2H), 1.28 (m, 10H), 0.88 (t, 3H)
With C96H110Cl4OP4Ru2; hydrogen; sodium tetraphenyl borate In toluene at 160℃; for 48h; Autoclave; Inert atmosphere;
1-2 Example 1-2
General procedure: To a dried glass tube (30 mL), a stirring bar, 3-phenylpropionic acid (150.2 mg, 1.0 mmol), the ruthenium complex 2 a obtained in Synthesis Example 1 (17.5 mg, 0.010 mmol), tetraphe Sodium nybborate (34.2 mg, 0.10 mmol) was charged and a tube containing this mixture was inserted into the autoclave. Subsequently, the interior of the autoclave was replaced with an argon gas atmosphere After that, dehydrated toluene (3.0 mL) was added while continuing the flow of argon gas. Hydrogen gas was introduced into the autoclave from a hydrogen gas cylinder connected via a stainless steel pipe, and the interior of the autoclave was replaced with hydrogen gas. That is, a hydrogen gas pressure of 1.5 MPa was applied to the autoclave, and then the hydrogen gas pressure was withdrawn from the leak valve. This operation (substitution-desorption) was repeated ten times. Finally, the hydrogen gas pressure in the autoclave was set to 4 MPa, and using a constant temperature bath, 160 ° C. for 24 hours.After completion of the reaction, the autoclave was immersed in an ice bath and cooled to near room temperature. Then, the leak valve of the autoclave was gently opened, and the hydrogen gas inside was released into the air. Next, the tube was taken out from the autoclave to obtain a reaction product (solution). This solution was transferred to a 100 mL recovery flask using chloroform and then concentrated under reduced pressure with an evaporator. For 1 H NMR analysis, an internal standard substance (mesitylene) was added. The hydrogen atomic weight of this internal standard substance , The yield of the reaction product was calculated. As a result, the yields of 3-phenylpropyl alcohol and 3-phenylpropyl 3-phenylpropionate were 65% and 12%, respectively.The same as in Example 1-1, except that the conditions described in Table 1 were adopted for the substrate, the ruthenium complex, the additive (alkali metal salt), and the hydrogenation conditions in Example 1-1 , And reduction (hydrogenation) was carried out. Materials other than the ruthenium complex 2a synthesized in Synthesis Example 1 were commercially available or synthesized by a known method. The results are shown in Table 1
19 Preparation of 2-butyloctyl nonanoate
Example 19 Preparation of 2-butyloctyl nonanoate 2-butyloctanol (13.1 g, 0.0704 mol, MW: 186.3), nonanoic acid (10 g 0.0640 mol, MW: 156.24) and titanium (VI) isopropoxide (0.910 g, 0.00320 mol, MW: 284.22) were mixed 75 ml toluene in three necked round bottom flask along with a dean-stark apparatus. Then solution was reflux for overnight (18 h). In 18 hours, ˜2 ml water was collected in the trap. Toluene was removed by simple distillation at 50° C. and excess of 2-butyloctanol was distilled with air bath oven at 180° C. under high vacuum and filter through celite. The isolated product was characterized by 1HNMR. Yields: 18 g (85%).
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In water; acetonitrile at 37℃; for 2.5h;
With 7CeO2*7Nb2O5*3La2O3*K2O*2Bi2O3; oxygen at 120℃; for 15h; Autoclave;
5 Example 5. Catalytic oxidation of methyl oleate (>99%) with the mixed oxide 7(CeO2) 7(Nb2O5) 3(La2O3) 1(K2O) 2(Bi2O3) under P02 = 9 bar.
In order to improve the stability of the catalyst and its activity, multiple mixed oxides were prepared. The mixed oxide 7(CeO2) 7(Nb2O5) 3(La2O3) 1(K2O) 2(Bi2O3), prepared according to Example 1 , showed excellent stability in catalysis and good reaction rate and selectivity. The catalyst (50 mg) was placed in a glass reactor, kept in vacuo for 30 min to eliminate humidity and added with methyl oleate (1 mL ) under N2. The reactor was placed in a stainless steel autoclave that was closed, evacuated, charged with O2 (9 bar) and heated to T=120 °C for a time variable between t=0,66 and 15h. At the end the catalyst was recovered by centrifugation and the liquid processed as reported in Example 3.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
Into a reactor equipped with a heating, stirring, and a thermometer, 112 g of vanillin amine hydrochloride obtained above was added to 670 ml of a DMF solvent, and the mixture was stirred at room temperature until the solid was completely dissolved and 95.2 g Nonanoic acid was added thereto.The was cooled to 0C with an ice bath, 134.4g of triethylamine was added, the temperature was stabilized at 0-5C, and 235.2g of a condensing agent HBTU was added under stirring. The reaction was naturally warmed to room temperature and stirred overnight. After the reaction was completely detected by TLC, Add 1100 ml of ethyl acetate and 330 ml of water to the reaction mixture. Stir well and place in liquid in a separatory funnel. Discard the aqueous layer and obtain ethyl acetate layers of 5 wt% sodium bicarbonate solution, 2 wt% hydrochloric acid, respectively. The saturated brine was washed three times each, 1200 ml/time, and then 100 g of anhydrous sodium sulfate was added to the ethyl acetate layer for drying for 3 hours. The sodium sulfate was removed by filtration, and the filtrate was placed in a reactor and heated to 45 C. with stirring and reduced. About 820 ml of ethyl acetate was distilled off and cooled to room temperature. 540 ml of petroleum ether was added to crystallize for 3 hours and filtered. The solid was dried at 40-45 C. for 10 hours to obtain 156.4 g of Nonivamide as the target product. The total yield was 81.1%. The obtained capsaicin was analyzed by HPLC and its purity was 98.8%.
With sulfur trioxide pyridine complex In 1,2-dichloro-benzene at 160℃; Schlenk technique; Inert atmosphere;
General procedure for SO3-medaiated amidation reaction and characterizationdata of the amides
General procedure: A typical procedure for the reaction of 4-trifluoromethylbenzoic acid 1a is described.A magnetic stirrer bar was placed in a Schlenk tube. This tube was then dried with aheat gun under reduced pressure and the test-tube was filled with nitrogen. 1a (19.0 mg,0.100 mmol) and SO3. py (63.7 mg, 0.400 mmol) were added to the test tubesuccessively under nitrogen atmosphere at room temperature. DMF (0.5 mL) orDMF(0.2 mL) - 1,2-dichlorobenzene(0.3 mL), were added to the tube. After beingstirred for 2 h at 160 °C, the mixture was filtered through a short silica gel pad (ca. 3.5cm × 0.5 cm, eluent AcOEt (60 mL)). The filtrate was concentrated under reducedpressure, and the residue was further dried in vacuo (ca. 7-8 mmHg at 70-80 °C) toremove DMF (and 1,2-dichlorobenzene). The residue was purified by preparative thinlayer chromatography on silica gel (AcOEt / hexane = 1 / 2) to give 20.8 mg (0.0959mmol, 96%) of 2a as colorless oil)
Oleyl alcohol (100 ml) is dissolved in propanoic acid (200 ml) in a jacketed reactor equipped with a gas sparger and an overhead stirrer. The reaction mixture is cooled to 10C while stirring and an 03/air mixture is sparged through the reactor over the course of 100 minutes until all olefin has been consumed, making sure that the internal temperature does not exceed 15C. The peroxide value of the mixture is tested using iodometric titration and is calculated to be 450 mmol/L. (0192) [00056] This mixture is then pumped through a " OD tube packed with sand mixed with 5% by wt. V2O5 that is kept at 90C. The flow rate is established such that the residence time in the packed tube is less than 15 minutes. After the material has passed through the tube, another peroxide test is performed the peroxide value was calculated to be 40 mmol/L. (0193) [00057] This mixture is then collected, charged with 250 mg of V2O5, and is sparged with oxygen at between 70 and 80C for several hours until lH NMR shows no more aldehyde peak to be present. Finally, the propanoic acid solvent is removed via distillation, resulting in a mixture of nonanoic acid, 9-hydroxynonanoic acid, and corresponding esters. The NMR data for this mixture is provided in Figure 2. The resulting mixture from Example 5 (86 g) is charged with Amberlyst cationic resin beads (~2 g) and is distilled at reduced pressure 0.5-2 mbar and 100C for 4 hours.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 24h;
1,10-Phenanthrolin-5-amine (0.5g, 2.56mmol) was dissolved in distilled dichloromethane (100mL) before the solution was cooled to 0C. Nonanoic acid (0.4g, 2.56mmol), EDCI (1.23g, 6.4mmol) and DMAP (0.31g, 2.56mmol) were added sequentially before the reaction mixture was stirred at 0C for another hour. The mixture was allowed to react at room temperature and stirred for 24h. The solvent was removed under reduced pressure and then purified by silica gel column chromatography using gradient elution of CH2Cl2/51 CH3OH (0 to 10%). Yield: 0.38g (47%). 1H NMR (400MHz, CDCl3) delta: 9.08 (dd, 2H), 8.29 (s, 1H), 8.11 (dd, 2H), 7.57 (dd, 2H), 2.55 (m, 2H), 1.82 (m, 3H), 1.29 (m, 10H), 0.89 (m, 3H). 13C NMR (100MHz, CDCl3), 172.59, 150.00, 149.54, 146.08, 143.98, 136.15, 128.36, 124.21, 123.51, 122.79, 119.89, 37.57, 29.37, 29.17, 25.75, 22.65, 14.11. HRMS found (calcd) for C21H24N3O (m/z): [M-H]-, 334.1903 (334.1919).
With 2,3,4,5,6-pentahydroxy-hexanal; cytochrome b5; glucose dehydrogenase from Bacillus megaterium; human cytochrome P450 monooxygenase; rat cytochrome P450 reductase; 1,2-dilauroyl-sn-glicero-3-phosphatidylcholine; NADPH; superoxide dismutase; catalase from bovine liver; In aq. phosphate buffer; dimethyl sulfoxide; at 30℃;pH 7.5;Enzymatic reaction;
General procedure: Conversions of fatty acids 1-8 and fatty alcohols 9-12 were carried out in 50mM potassium phosphate buffer, pH 7.5 and a total reaction volume of 100muL. Reaction mixtures contained 0.25muM CYP4B1, 0.5muM CPR, 0.25muM cytochrome b5, 100 U mL-1 superoxide dismutase, 1000 UmL-1 catalase, 25 U mL-1 GDH, 20mM glucose, 25mugmL-1 DLPC, 200muM substrate (from a 10mM stock solution dissolved in DMSO) and 200muM NADPH. Samples were incubated at 30C for 90min; this reaction time was chosen as an almost complete substrate conversion (as achieved for C12 4 after 120min) was not desirable, so as to allow comparison of the conversion values for the individual substrates and also between the two CYP4B1 isoforms.
With boron trifluoride dihydrate at 120℃; for 0.416667h; Microwave irradiation;
Synthesis of acylhydroquinones III-VI
General procedure: The already reportedmethodology of obtention of acyl hydroquinones [35] wasimproved using microwave irradiation as follows. To a 10 mL CEMmicrowave process vial, equipped with a magnetic stir bar, wereadded one equivalent of hydroquinone (I) or dimethylhydroquinone (II), 1.5 equivalent of carboxylic acid and 4 mL ofboron trifluoride dihydrate. The mixture was irradiated under microwavefor 25 min at 120 C. After completion of the reaction, themixture was allowed to cool to room temperature (RT) andextracted with ethyl acetate, the organic phase was washed withdistilled water and dried with anhydrous sodium sulfate, then wasfiltered and concentrated under vacuum. Afterward, acylhydroquinonesIII-VI were purified by flash chromatography with 6:1hexane/ethyl acetate as eluent.
46.4%
With boron trifluoride dihydrate at 90℃; for 0.333333h; Microwave irradiation;
2.2.1. General procedure for the synthesis of acylhydroquinones 3-20
General procedure: The synthetic methodology to obtain the studied compounds 3-20 isdepicted in Scheme 1. The already reported methodology of obtentionof acylhydroquinones [30] was improved using microwave irradiationat 90 °C, at a fixed power of 150 W as follows. To a 10 mL CEM microwaveprocess vial equipped with a stir bar were added one equivalentof hydroquinone, 1.5 equivalent of carboxylic acid and 4 mL ofBoron trifluoride dihydrate. The mixture was irradiated under microwaveby 20 min. The mixture was allowed to cool to room temperature,extracted with ethyl acetate, the extract washed with distilled waterand dried with anhydrous sodium sulfate, then was filtered and concentratedunder vacuum. Afterward, the corresponding acylhydroquinonewas purified by flash chromatography with hexane/ethylacetate 4:1 as eluent. in this manner were obtained the acylhydroquinones3-11. Compounds 12-20 were obtained by chlorination,with hydrogen chloride, of the respective quinones obtained by oxidationof the hydroquinones 3-11, with Ag2O in dichloromethane [26],these compounds also were purified by flash chromatography withhexane/ethyl acetate 4:1 as eluent. The 1H NMR and 13C NMR spectradata for acylhydroquinones 3-20 are provided in the supplementaryinformation.
With boron trifluoride dihydrate for 0.333333h; Microwave irradiation;
2.2. Synthesis of acylhydroquinones and acylchlorohydroquinones
General procedure: The synthetic methodology for obtaining acylhydroquinones hasbeen already reported [29,30] and was used to synthesize the compounds13-27 (Table 1). Briefly, acylhydroquinones 13-27 were obtainedusing microwave irradiation at 90 C, at a fixed power of 150 Was follows. To a 10 mL CEM microwave (CEM Discovery SP Labmate, NC,USA) process vial equipped with a magnetic bar, a mixture of oneequivalent of hydroquinone was added (1) or dimethyl hydroquinone(2), 1.5 equivalent of the corresponding carboxylic acid (3-11), and 4mL of boron trifluoride dihydrate (Sigma-Aldrich, DA, Germany). Themixture was irradiated under microwave for 20 min. After that, themixture was extracted with ethyl acetate (Panreac Quimica, BCN,Spain), washed with water, and dried with anhydrous sodium sulfate(Sigma-Aldrich, DA, Germany), then it was filtered and concentratedunder vacuum. Afterward, the corresponding acylhydroquinone waspurified by flash chromatography with hexane/ethyl acetate (PanreacQuimica, BCN, Spain) 4:1 as eluent. In this manner, the acylhydroquinones13-27 were obtained. As shown in Table 1, compounds28-38 were obtained by chlorination, with hydrogen chloride (obtainedby reaction of concentrated sulfuric acid with sodium chloride) [31] ofthe corresponding quinones obtained by oxidation of the hydroquinones12-15, 17-22, and 24, with Ag2O (obtained by adding concentratedsodium hydroxide to a silver nitrate solution) [32] in dichloromethane(Merck, DA, Germany) [29], these compounds were also purified byflash chromatography with hexane/ethyl acetate 4:1 as eluent.
1-(2,5-dihydroxy-3,4-dimethylphenyl)nonan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With boron trifluoride dihydrate at 90℃; for 0.333333h; Microwave irradiation;
2.2.1. General procedure for the synthesis of acylhydroquinones 3-20
General procedure: The synthetic methodology to obtain the studied compounds 3-20 isdepicted in Scheme 1. The already reported methodology of obtentionof acylhydroquinones [30] was improved using microwave irradiationat 90 °C, at a fixed power of 150 W as follows. To a 10 mL CEM microwaveprocess vial equipped with a stir bar were added one equivalentof hydroquinone, 1.5 equivalent of carboxylic acid and 4 mL ofBoron trifluoride dihydrate. The mixture was irradiated under microwaveby 20 min. The mixture was allowed to cool to room temperature,extracted with ethyl acetate, the extract washed with distilled waterand dried with anhydrous sodium sulfate, then was filtered and concentratedunder vacuum. Afterward, the corresponding acylhydroquinonewas purified by flash chromatography with hexane/ethylacetate 4:1 as eluent. in this manner were obtained the acylhydroquinones3-11. Compounds 12-20 were obtained by chlorination,with hydrogen chloride, of the respective quinones obtained by oxidationof the hydroquinones 3-11, with Ag2O in dichloromethane [26],these compounds also were purified by flash chromatography withhexane/ethyl acetate 4:1 as eluent. The 1H NMR and 13C NMR spectradata for acylhydroquinones 3-20 are provided in the supplementaryinformation.
With boron trifluoride dihydrate for 0.333333h; Microwave irradiation;
2.2. Synthesis of acylhydroquinones and acylchlorohydroquinones
General procedure: The synthetic methodology for obtaining acylhydroquinones hasbeen already reported [29,30] and was used to synthesize the compounds13-27 (Table 1). Briefly, acylhydroquinones 13-27 were obtainedusing microwave irradiation at 90 C, at a fixed power of 150 Was follows. To a 10 mL CEM microwave (CEM Discovery SP Labmate, NC,USA) process vial equipped with a magnetic bar, a mixture of oneequivalent of hydroquinone was added (1) or dimethyl hydroquinone(2), 1.5 equivalent of the corresponding carboxylic acid (3-11), and 4mL of boron trifluoride dihydrate (Sigma-Aldrich, DA, Germany). Themixture was irradiated under microwave for 20 min. After that, themixture was extracted with ethyl acetate (Panreac Quimica, BCN,Spain), washed with water, and dried with anhydrous sodium sulfate(Sigma-Aldrich, DA, Germany), then it was filtered and concentratedunder vacuum. Afterward, the corresponding acylhydroquinone waspurified by flash chromatography with hexane/ethyl acetate (PanreacQuimica, BCN, Spain) 4:1 as eluent. In this manner, the acylhydroquinones13-27 were obtained. As shown in Table 1, compounds28-38 were obtained by chlorination, with hydrogen chloride (obtainedby reaction of concentrated sulfuric acid with sodium chloride) [31] ofthe corresponding quinones obtained by oxidation of the hydroquinones12-15, 17-22, and 24, with Ag2O (obtained by adding concentratedsodium hydroxide to a silver nitrate solution) [32] in dichloromethane(Merck, DA, Germany) [29], these compounds were also purified byflash chromatography with hexane/ethyl acetate 4:1 as eluent.
With cobalt(II) oxide; N,N,N,N,-tetramethylethylenediamine; oxygen In water at 100℃; for 35h;
5 Example 5
Add 1-nonanol (23.08g, 160mmol), cobalt oxide (0.07g, 1.0mmol), N,N,N'N into a 250ml pressure-resistant reactor with quartz lining (equipped with a back pressure valve) '-Tetramethylethylenediamine (0.12g, 1.0mmol), 58ml of water, then use oxygen to replace the air in the reactor, and continue to ventilate to control the pressure in the kettle to 1.8Mp, maintain the pressure and continue to inject oxygen into it. Stir under reflux for 35 hours at 100°C. After the reaction, the reaction liquid is cooled to room temperature, filtered to remove the solid material, the liquid is separated by distillation to obtain the product 1-nonanoic acid and the product 1-nonene, the conversion rate of 1-nonanol is 87%, and the yield of 1-nonanoic acid It was 50%, and the yield of 1-nonene was 32%.
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